Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses.

Influence of the Envelope gp120 Phe 43 Cavity on HIV-1 Sensitivity to Antibody-Dependent Cell-Mediated Cytotoxicity Responses.

Products Related

Product# 101 gp120 Capture Elisa Kit

Product# 1081 HIV-1 gp120 (ADA)

Product# 1011 HIV-1 gp120 (subtype C)

INTRODUCTION

Entry is the first step of the human immunodeficiency virus type 1 (HIV-1) replication cycle and requires the mature viral envelope glycoproteins (Env), which results from the proteolytic cleavage of the gp160 precursor Env into the exterior gp120 and transmembrane gp41 subunits. These subunits are linked by noncovalent bonds, allowing conformational changes of the Env trimer during the entry process (1,–3). The gp120 exterior subunit mediates the initial interaction with the CD4 receptor. gp120 residue 375 is located in what is known as the Phe 43 cavity, where Phe 43 of CD4 makes numerous contacts with conserved gp120 residues critical for CD4 binding (4). Some gp120 residues that line this cavity contribute to an aromatic array that helps stabilize the CD4-bound conformation (1, 4, 5). Upon CD4 binding, major conformational changes expose the binding site for coreceptor (i.e., CCR5 and CXCR4) interaction (6). Upon coreceptor engagement, additional conformational changes in gp41 bring together the viral envelope and the target cell membranes (7, 8). It has been shown that some of these conformational rearrangements could be impacted by large alterations in the Phe 43 cavity. The replacement of the well-conserved group M serine at position 375 by a large hydrophobic residue such as tryptophan fills the Phe 43 cavity; this substitution alters the Env conformation by predisposing gp120 to spontaneously assume a state closer to the CD4-bound conformation (9). In agreement with the important role played by Env conformation in the CD4 interaction (1, 9,–11), a recent study using the simian-human immunodeficiency virus (SHIV) model in rhesus macaques showed that the replacement of residue 375 by larger hydrophobic or basic amino acids enhanced the affinity of Env for macaque CD4 and allowed better infection of macaque T lymphocytes in culture and in vivo (12), highlighting the importance of this residue for viral replication.

Besides its potential involvement in viral replication, the CD4-bound conformation of HIV-1 Env represents a major target of antibodies (Abs) present in sera of HIV-1-infected individuals that mediate antibody-dependent cellular cytotoxicity (ADCC) (13). It has been shown that HIV-1 minimizes the exposure of this ADCC-susceptible Env conformation using a highly sophisticated strategy to keep Env on the surface of infected cells in the unbound “closed” conformation. HIV-1 accomplishes this through its accessory proteins Nef and Vpu, which decrease the overall amounts of Env (via Vpu-mediated BST-2 downregulation) and CD4 at the cell surface (13,–16). In addition, decreased amounts of Env at the cell surface due to efficient internalization also help the virus to avoid ADCC responses (17). In agreement with the need for HIV-1 to avoid exposing Env in the CD4-bound conformation, it was recently shown that forcing Env to adopt this conformation with small CD4-mimetic compounds (CD4mcs) sensitizes HIV-1-infected cells to ADCC responses (18,–20). Accordingly, we recently reported that the transition of Env to the CD4-bound conformation is required for efficient interactions with ADCC-mediating antibodies (14). We reported that the replacement of serine 375 by a tryptophan residue (S375W) enhanced the exposure of epitopes recognized by anti-cluster A antibodies, known to mediate potent ADCC responses (13, 14, 18, 20,–26). Thus, the transition of Env from the unbound to the CD4-bound conformation appears to be a prerequisite for the exposure of inner-domain ADCC epitopes. However, how the presence of naturally occurring Phe 43 cavity-filling residues affects ADCC responses remains unknown.

While Ser 375 is well conserved in the majority of group M HIV-1 isolates, we noticed that CRF01_AE Env possess a Phe 43 cavity-filling residue at position 375 (His 375) (27). CRF01_AE is the predominant circulating strain in Thailand, where the RV144 clinical vaccine trial took place. In this trial, which resulted in a modest degree of clinical protection, ADCC responses were identified as a correlate of protection (28), raising the intriguing possibility that naturally occurring His 375 in CRF01_AE Env might have contributed to this outcome. Here we explored the influence of the integrity of the Phe 43 cavity on ADCC responses.

Go to:

RESULTS

 

Comparison of residue 375 flanking the Phe 43 cavity among HIV-1 strains.

The vast genetic variability of HIV-1 resulted in its classification into 4 major groups, groups M, N, O, and P. Group M, or “main” group, viruses are responsible for the majority of the global HIV-1 pandemic. Group M is comprised of nine major subtypes and circulating recombinant forms (CRFs) (29,–33). To determine the variance in residue 375 among HIV-1 Env, we analyzed all available group M sequences in the NIH Los Alamos HIV database. Interestingly, while the vast majority (>84%) of group M strains have a serine at position 375 (S375) and another 9% have a closely related T375 substitution (Fig. 1A to ​toDD and ​andFF to ​toH),H), nearly all CRF01_AE Env have a large basic aromatic histidine residue at this position. Indeed, alignments revealed >99% conservation for H375 in CRF01_AE strains (Fig. 1E), clearly differentiating them from the other circulating strains of group M.

 

An external file that holds a picture, illustration, etc.
Object name is zjv9991824570003.jpg

FIG 3

The Phe 43 cavity modulates ADCC responses mediated by the A32 antibody and antibodies within HIV+ sera. Primary CD4+ T cells infected with NL4.3-GFP expressing the primary R5 ADA Env (clade B) or SHIV expressing either CH505 (clade C) or 191859 (clade D) Env were used as target cells and autologous PBMCs were used as effector cells in our FACS-based ADCC assay, as described in Materials and Methods. Shown are the percentages of ADCC activity in the presence of anti-cluster A monoclonal antibody A32 (A to C) or in the presence of HIV+ sera from HIV-1 clade B-infected individuals (D to F). These results are representative of those obtained in at least 3 independent experiments. Error bars indicate means ± standard errors of the means. Statistical significance was tested by using paired one-way analysis of variance with a Holm-Sidak posttest (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001; ns, nonsignificant).

 

The Phe 43 cavity modulates recognition of CRF01_AE HIV-1-infected cells by CD4i antibodies and HIV+ sera.

CRF01_AE HIV-1 isolates have a highly conserved histidine residue at Env position 375 (Fig. 1E), which was recently shown to be important for CD4 interaction (27) but also to confer strong resistance to the BMS-599793 entry inhibitor (36). To evaluate whether His 375 influences the recognition of infected cells by ADCC-mediating antibodies and HIV+ sera, His 375 in the CRF01_AE703357 strain was replaced by a serine (H375S). This strain was identified in the RV144 cohort and submitted to GenBank.

CRF01_AE IMCs were used to infect primary CD4+ T cells from healthy uninfected donors. The impact of residue 375 on Env conformation was evaluated with CD4i 17b and A32 antibodies as well as sera from clade B- and CRF01_AE-infected individuals. The nature of the residue at position 375 did not affect CD4 downregulation (Fig. 4A) or Env expression, as evaluated by the binding of the 10e8 antibody (Fig. 4B). In contrast to the limited recognition of clade B, C, and D HIV-1-infected cells by A32, 17b, and antibodies within HIV+ sera (Fig. 2) (13, 18, 20, 22, 37), cells infected with wild-type CRF01_AE Env (H375) were better recognized by both CD4i monoclonal antibodies (MAbs) as well as polyclonal sera (Fig. 4C to ​toF).F). Strikingly, the replacement of His 375 by a serine residue (H375S) significantly decreased the recognition of infected cells by these ligands (Fig. 4). Overall, these results suggest that the recognition of wild-type CRF01_AE HIV-1 by CD4i antibodies and antibodies within HIV+ sera is enhanced by the Phe 43 cavity-filling histidine residue at 375. H375 functions as a proxy of small CD4mcs, which were recently shown to push Env into the CD4-bound conformation and sensitize HIV-1-infected cells to ADCC (18).

 

FIG 4

The Phe 43 cavity modulates the recognition of CRF01_AE HIV-1-infected primary CD4+ T cells by CD4i antibodies and HIV+ sera. Shown are data for cell surface staining of primary CD4+ T cells that were either mock infected or infected with the WT or the H375S variant of CRF01_AE transmitted-founder HIV-1 (IMC 703357) with anti-CD4 antibody OKT4 (A), conformation-insensitive Env-specific antibody 10e8 (B), CD4i antibodies 17b (C) and A32 (D), and sera from individuals infected with HIV-1 clade B (E) or HIV-1 CRF01_AE (F). Shown are the MFIs obtained in at least 4 independent experiments. Error bars indicate means ± standard errors of the means. Statistical significance was tested by using an unpaired two-tailed t test for MAbs or a paired two-tailed t test for HIV+ sera (*, P < 0.05; ****, P < 0.0001; ns, nonsignificant).

 

The Phe 43 cavity modulates recognition of CRF01_AE HIV-1-infected cells by serum antibodies isolated from RV144 vaccinees.

A correlation between high levels of ADCC-mediating antibodies and HIV-1 acquisition in the RV144 vaccine trial was suggested for a subset of individuals with low plasma IgA anti-Env antibody levels (26, 28). ADCC-mediating MAbs targeting multiple epitopes were isolated from memory B cells of RV144 vaccine recipients (26, 38). Importantly, we demonstrated that the vaccine-induced ADCC-mediating antibodies directed against A32-blockable conformational epitopes poorly recognize Env on the surface of HIV-1-infected cells (clade B) unless the CD4 receptor was present on the surface of infected cells. This was achieved by deleting the nef and vpu genes (14). Since the predominantly circulating strain in Thailand is a CRF01_AE HIV-1 strain, which has a histidine at residue 375, we asked whether these antibodies, thought to have protected against HIV-1 transmission in RV144 recipients, recognized CRF01_AE HIV-1-infected cells in a manner dependent on Env residue 375. Wild-type (H375) or H375S mutant CRF01_AE IMCs were used to infect primary CD4+ T cells from healthy uninfected donors. Figure 5 shows that 11/12 (91.7%) A32-blockable antibodies induced by the RV144 vaccine recognized CRF01_AE HIV-1-infected cells expressing wild-type Env H375 significantly better than they recognized cells infected with the H375S counterpart.

 

FIG 5

The Phe 43 cavity modulates the recognition of CRF01_AE HIV-1-infected primary CD4+ T cells by antibodies isolated from RV144 vaccinees. Shown are data for cell surface staining of primary CD4+ T cells that were either mock infected or infected with the WT or an H375S mutant of CRF01_AE transmitted-founder HIV-1 (IMC 703357) with A32-blockable MAbs isolated from RV144 vaccinees (CH29, CH38, CH40, CH51, CH52, CH54, CH77, CH80, CH81, CH89, CH91, and CH94). Shown are the MFIs obtained in at least 5 independent experiments. Error bars indicate means ± standard errors of the means. Statistical significance was tested by using an unpaired two-tailed t test (*, P < 0.05; **, P < 0.01; ****, P < 0.0001).

 

Residue 375 modulates ADCC responses against CRF01_AE HIV-1-infected cells by CD4i antibodies, antibodies within HIV+ sera, and antibodies from RV144 vaccinees.

To assess whether the recognition of CRF01_AE HIV-1-infected cells by A32, antibodies within HIV+ sera, and antibodies from RV144 vaccinees correlated with ADCC responses, primary CD4+ T cells were infected as described above, and ADCC was measured as described in Materials and Methods. Figure 6 shows that wild-type (H375) CRF01_AE HIV-1-infected cells were readily susceptible to ADCC mediated by A32 and antibodies within HIV+ sera from individuals infected with clade B and CRF01_AE HIV-1 strains. This result contrasts with the relatively poor ADCC activity observed for these antibodies against primary CD4+ T cells infected with wild-type (S375) HIV-1 strains from clades B, C, and D (Fig. 3). ADCC responses directed against CRF01_AE HIV-1-infected cells depended on the presence of His 375, as cells infected with the H375S virus variant were significantly less sensitive to ADCC. Similar results were observed when ADCC experiments were done using the majority of RV144 anti-cluster A antibodies (CH29, CH38, CH40, CH51, CH52, CH54, CH77, CH80, and CH94) (Fig. 7).

 

FIG 6

Histidine 375 modulates ADCC responses against CRF01_AE HIV-1-infected cells mediated by the A32 antibody and HIV+ sera. Primary CD4+ T cells infected with WT and H375S mutant CRF01_AE transmitted-founder HIV-1 (IMC 703357) were used as target cells and autologous PBMCs were used as effector cells in our FACS-based ADCC assay, as described in Materials and Methods. Shown are the percentages of ADCC activity by A32 (A) or by antibodies in sera from HIV-1 clade B-infected (B) or CRF01_AE HIV-1-infected (C) individuals. These results are representative of data from at least 4 independent experiments. Error bars indicate means ± standard errors of the means. Statistical significance was tested by using an unpaired two-tailed t test for A32 or a paired two-tailed t test for HIV+ sera (***, P < 0.001; ****, P < 0.0001).

An external file that holds a picture, illustration, etc.
Object name is zjv9991824570007.jpg

FIG 7

Histidine 375 modulates ADCC responses against CRF01_AE HIV-1-infected cells mediated by antibodies isolated from RV144 vaccinees. Primary CD4+ T cells infected with the WT or the H375S variant of CRF01_AE transmitted-founder HIV-1 (IMC 703357) were used as target cells, with autologous PBMCs as effector cells, in our FACS-based ADCC assay. Shown are the percentages of ADCC activity in the presence of the A32-blockable monoclonal antibodies (CH29, CH38, CH40, CH51, CH52, CH54, CH77, CH80, CH81, CH89, CH91, and CH94) isolated from RV144 vaccinees. These results are representative of those obtained in at least 5 independent experiments. Error bars indicate means ± standard errors of the means. Statistical significance was tested by using an unpaired two-tailed t test (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001).

Go to:

DISCUSSION

Renewed interest in the Fc-mediated functions of antibodies such as ADCC stems in part from observed correlations with the control or prevention of HIV-1 infection. Fc-mediated effector functions were found to inversely correlate with viral loads or disease progression in simian immunodeficiency virus (SIV)-infected macaques (39,–41) as well as in HIV-1-infected individuals (42,–46). Furthermore, analysis of correlates of immune protection in the recent RV144 vaccine trial suggested that high levels of ADCC-mediating Abs correlated with decreased HIV-1 acquisition when combined with low plasma IgA anti-Env antibody levels (28, 47). Moreover, the CD4-bound conformation of Env was recently shown to be a major target of ADCC-mediating antibodies present in the sera of HIV-1-infected individuals (13). Accordingly, here we report that the size of the residue located within the Phe 43 cavity of Env modulates the recognition and killing of HIV-1-infected cells by antibodies within HIV+ sera and ADCC-mediating monoclonal antibodies, including those isolated from RV144 vaccinees. Altogether, our results suggest a model (Fig. 8) where the conformation spontaneously sampled by Env at the surface of infected cells has a significant impact on ADCC susceptibility. Env with an empty Phe 43 cavity are protected from such responses due to the adoption of a conformation similar to that of the unliganded closed state (state 1) and the ability of Nef and Vpu to downregulate CD4 from the cell surface (14). This state 1 conformation of Env could be modulated by CD4mcs (18) or by naturally occurring Phe 43 cavity-filling residues, which shift Env conformation toward the CD4-bound state. The CD4-bound Env conformation efficiently exposes anti-cluster A epitopes, known to be recognized by antibodies present in the majority of HIV-1-infected individuals and to mediate potent ADCC responses (13, 14, 18, 20,–26). Therefore, our results raise the intriguing possibility that histidine 375 present in the predominant strain replicating in Thailand might have contributed to the efficacy of the trial by spontaneously exposing epitopes recognized by ADCC-mediating antibodies elicited by the RV144 vaccine regimen.

 



 

An external file that holds a picture, illustration, etc.
Object name is zjv9991824570008.jpg

FIG 8

The Phe 43 cavity modulates HIV-1 Env conformation and ADCC responses. Flanking the Phe 43 cavity, the identity of residue 375 modulates the transition of Env to the CD4-bound conformation. The presence of a serine residue at this position keeps Env in its unliganded, closed state (state 1), thus preventing the exposure of highly conserved epitopes recognized by anti-cluster A antibodies. The presence of a larger residue within the cavity, such as the naturally occurring histidine at position 375, shifts Env conformation to a state closer to the CD4-bound state, thus more readily exposing cluster A epitopes and enhancing the susceptibility of infected cells to ADCC mediated by antibodies in HIV+ sera.

Since the first emergence of CRF01_AE HIV-1 strains in Africa and subsequent spread to Asia, where it established a major epidemic, this virus has become the dominant strain in many Asian countries, including southern China and Thailand (48,–50). Why CRF01_AE HIV-1 was able to spread so rapidly is unclear at the moment, but high viral loads and short survival times have been associated with CRF01_AE infection compared with the values seen for HIV-1 infections in the Western world (51,–53). Additional work is needed to assess the evolutionary selective pressures that resulted in the fixation of a histidine residue at position 375 in this rapidly spreading viral strain. Substitutions of large residues like histidine at this position have been shown to result in SHIVs that bind rhesus macaque CD4 and replicate in monkeys more efficiently (12). Apparently, the advantages of the S375W change in specific hosts (rhesus monkeys and some southern Chinese and Thai individuals) outweigh negative consequences such as enhanced susceptibility of HIV-1-infected cells to ADCC responses. Our results warrant further studies that assess potential host factors that drive HIV-1 variation in the Phe 43 cavity. The importance of the variation in residue 375 to susceptibility to the protective efficacy of HIV-1 vaccine-induced antibody responses also merits additional investigation.

Go to:

MATERIALS AND METHODS

 

Plasmids and site-directed mutagenesis.

Individual Env mutations were introduced in the previously described pNL43-ADA(Env)-GFP.IRES.Nef proviral vector (14) by using the QuikChange II XL site-directed mutagenesis protocol (Stratagene). The plasmids encoding SHIV clade C strain CH505, SHIV clade D strain 191859, and their variants were previously described (12). The sequence of HIV-1 CRF01_AE transmitted-founder (T/F) clone 703357 was derived by using a single-genome amplification (SGA) strategy. The entire DNA sequence including both long terminal repeats (LTRs) was cloned into pUC57 to generate a full-length infectious molecular clone (FLIMC) (GenBank accession numbers JX448154 and JX448164). Single mutations were then introduced into FLIMC 703357.

 

Cell lines and isolation of primary cells.

293T human embryonic kidney cells were obtained from the ATCC and were grown as previously described (14). PBMCs from healthy donors were obtained under research regulations approved by the Centre de Recherche du CHUM (CRCHUM); written informed consent was obtained from each individual. CD4+ T cells were purified from rested PBMCs by negative selection and activated as previously described (18).

 

Virus production and infections.

In order to achieve the same level of infection among the different mutants tested, vesicular stomatitis virus G (VSVG)-pseudotyped HIV-1 clones were produced, as previously described (14). This was necessary since mutations at residue 375 were shown to affect CD4 binding and infectivity in CRF01_AE strains (27). Briefly, proviral vectors and a VSVG-encoding plasmid were cotransfected into 293T cells by standard calcium phosphate transfection. Two days after transfection, cell supernatants were harvested, clarified by low-speed centrifugation (5 min at 1,500 rpm), and concentrated by ultracentrifugation for 1 h at 4°C at 100,605 × g over a 20% sucrose cushion. Pellets were resuspended in fresh RPMI, and aliquots were stored at −80°C until use. Viruses were then used to infect ∼10 to 15% of primary CD4+ T cells by spinoculation at 800 × g for 1 h in 96-well plates at 25°C.

 

Antibodies and sera.

The gp120 outer-domain-specific 2G12 and the anti-gp41 10e8 antibodies were obtained from the NIH AIDS and Research and Reference Reagent Program. Anti-gp120 cluster A antibody A32 and coreceptor binding site antibody 17b were previously reported (14, 24, 54, 55). A32-blockable conformational epitope ADCC-mediating antibodies isolated from recipients of the RV144 ALVAC-HIV AIDSVAX B/E vaccine (CH29, CH38, CH40, CH51, CH52, CH54, CH77, CH80, CH81, CH89, CH91, and CH94) were previously described (14, 26). Sera from HIV-infected individuals (Table 1) were collected, heat inactivated, and stored as previously described (18). Written informed consent was obtained from all study participants (the Montreal Primary HIV Infection Cohort [56, 57] and the Canadian Cohort of HIV Infected Slow Progressors [58,–60]), and research adhered to the ethical guidelines of the CRCHUM and was reviewed and approved by the CRCHUM institutional review board (ethics committee). Additional serum samples were acquired from HIV-1-infected individuals from Thailand who were enrolled in the HIV STAR study, as previously described (61) (Table 2). The Thai Ministry of Public Health and local ethics committees approved the collection of these samples. All donors provided informed consent. Research adhered to the standards indicated by the Declaration of Helsinki. All sera were heat inactivated for 30 min at 56°C and stored at 4°C until they were ready for use in subsequent experiments. A random-number generator (QuickCalcs; GraphPad) was used to randomly select a number of serum samples for each experiment.

TABLE 1

Characteristics of HIV-infected serum donors

Donor

CD4 count (no. of cells/mm3)

Viral load (no. of copies/ml)

1

410

260

2

692

50

3

680

633

4

620

40

5

580

1,477

6

670

58,475

7

592

13,520

8

810

42

9

780

949

10

1,307

3,387

11

780

905

12

800

7,206

13

747

3,098

14

920

277

15

790

22,045

16

1,009

67

17

830

674

18

1,029

3,779

19

647

961

20

420

1,112

21

460

180,763

Open in a separate window

TABLE 2

Characteristics of HIV-1-infected Thai serum donors

Donor

CD4 count (cells/mm3)

Viral load (copies/ml)

1

436

29,600

2

200

87,300

3

775

<40

4

266

43,700

5

119

9,260

6

369

<50

7

505

2,470

8

208

<50

9

690

<50

10

358

<50

11

76

14,000

12

610

<40

13

519

<50

14

362

1,450

15

282

<50

16

488

67

17

180

<50

18

448

<40

19

424

61

20

273

<50

21

519

<50

22

388

<50

23

413

<40

Open in a separate window

Anti-CD4 monoclonal antibody OKT4 (BioLegend) binds to the D3 domain of CD4 and was used to measure cell surface levels of CD4, as described previously (14). Goat anti-mouse and anti-human antibodies coupled to Alexa Fluor 647 (Invitrogen) were used as secondary antibodies in flow cytometry experiments.

 

Flow cytometry analysis of cell surface staining and ADCC responses.

Cell surface staining was performed as previously described, and mean fluorescence intensity (MFI) histograms show signals on live infected populations (13, 18). Binding of HIV-1-infected cells by HIV+ sera (1:1,000 dilution) or anti-CD4 (OKT4) or anti-Env MAbs (5 μg/ml) was performed 48 h after in vitro infection. Detection of green fluorescent protein-positive (GFP+), p24+, or p27+ infected cells was performed as described previously (37). The percentage of infected cells (i.e., GFP+, p24+, or p27+ cells) was determined by gating the living cell population based on viability dye staining (Aqua Vivid, catalog number L43957; Thermo Fisher Scientific). Samples were analyzed on an LSRII cytometer (BD Biosciences, Mississauga, ON, Canada), and data analysis was performed by using FlowJo v10.0.7 (Tree Star, Ashland, OR, USA).

Measurement of ADCC-mediated killing was performed by using a previously described assay (18). Briefly, primary CD4+ T cells infected for 48 h with the different molecularly cloned viruses described above were incubated with autologous PBMCs (effector-to-target cell ratio of 10:1) in the presence of A32, RV144 antibodies (5 μg/ml), or HIV+ sera (1:1,000). The percentage of cytotoxicity was calculated as described previously (18).

 

Statistical analyses.

Statistics were analyzed by using GraphPad Prism version 6.01 (GraphPad, San Diego, CA, USA). P values of <0.05 were considered significant; significance values are indicated in the figure legends.

Go to:

ACKNOWLEDGMENTS

We thank Elizabeth Carpelan for help with manuscript preparation. We thank Dominique Gauchat from the CRCHUM Flow Cytometry Platform for technical assistance and Mario Legault for cohort coordination and clinical samples.

This work was supported by CIHR Foundation grant 352417, by amfAR innovation grant 109343-59-RGRL with support from FAIR to A.F., and by the FRQS AIDS and Infectious Diseases Network. A.F. is the recipient of a Canada research chair on retroviral entry. D.Z. is the recipient of FRQS master award 30888. M.V. was supported by CIHR doctoral research award 291485. J.R. is the recipient of CIHR fellowship award 135349. M.S.P. is the recipient of CIHR fellowship award 135451. D.E.K. is supported by a research scholar career award of the Quebec Health Research Fund (FRQS). This study was also supported by CIHR grant MOP93770, NIH grants AI100645 and AI100663, the Center for HIV/AIDS Vaccine Immunology and Immunogen Design (CHAVI-ID), National Institutes of Health grant GM56550, the late William F. McCarty-Cooper, and NIH grant R01AI116274. Our funding sources had no role in data collection, analysis, or interpretation and were not involved in the writing of the manuscript.

The opinions expressed here are those of the authors and should not be construed as official or representing the views of the U.S. Department of Defense or Department of the Army. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. government.

Go to:

REFERENCES

  1. Finzi A, Xiang SH, Pacheco B, Wang L, Haight J, Kassa A, Danek B, Pancera M, Kwong PD, Sodroski J. 2010. Topological layers in the HIV-1 gp120 inner domain regulate gp41 interaction and CD4-triggered conformational transitionsMol Cell37:656–667. doi:10.1016/j.molcel.2010.02.012. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  2. Helseth E, Olshevsky U, Furman C, Sodroski J. 1991. Human immunodeficiency virus type 1 gp120 envelope glycoprotein regions important for association with the gp41 transmembrane glycoproteinJ Virol65:2119–2123. [PMC free article] [PubMed] [Google Scholar]
  3. Yang X, Mahony E, Holm GH, Kassa A, Sodroski J. 2003. Role of the gp120 inner domain beta-sandwich in the interaction between the human immunodeficiency virus envelope glycoprotein subunitsVirology313:117–125. doi:10.1016/S0042-6822(03)00273-3. [PubMed] [CrossRef] [Google Scholar]
  4. Kwong PD, Wyatt R, Robinson J, Sweet RW, Sodroski J, Hendrickson WA. 1998. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibodyNature393:648–659. doi:10.1038/31405. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  5. Pancera M, Majeed S, Ban YE, Chen L, Huang CC, Kong L, Kwon YD, Stuckey J, Zhou T, Robinson JE, Schief WR, Sodroski J, Wyatt R, Kwong PD. 2010. Structure of HIV-1 gp120 with gp41-interactive region reveals layered envelope architecture and basis of conformational mobilityProc Natl Acad Sci U S A107:1166–1171. doi:10.1073/pnas.0911004107. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  6. Wyatt R, Moore J, Accola M, Desjardin E, Robinson J, Sodroski J. 1995. Involvement of the V1/V2 variable loop structure in the exposure of human immunodeficiency virus type 1 gp120 epitopes induced by receptor bindingJ Virol69:5723–5733. [PMC free article] [PubMed] [Google Scholar]
  7. Lu M, Blacklow SC, Kim PS. 1995. A trimeric structural domain of the HIV-1 transmembrane glycoproteinNat Struct Biol2:1075–1082. doi:10.1038/nsb1295-1075. [PubMed] [CrossRef] [Google Scholar]
  8. Weissenhorn W, Dessen A, Harrison SC, Skehel JJ, Wiley DC. 1997. Atomic structure of the ectodomain from HIV-1 gp41Nature387:426–430. doi:10.1038/387426a0. [PubMed] [CrossRef] [Google Scholar]
  9. Xiang SH, Kwong PD, Gupta R, Rizzuto CD, Casper DJ, Wyatt R, Wang L, Hendrickson WA, Doyle ML, Sodroski J. 2002. Mutagenic stabilization and/or disruption of a CD4-bound state reveals distinct conformations of the human immunodeficiency virus type 1 gp120 envelope glycoproteinJ Virol76:9888–9899. doi:10.1128/JVI.76.19.9888-9899.2002. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  10. Desormeaux A, Coutu M, Medjahed H, Pacheco B, Herschhorn A, Gu C, Xiang SH, Mao Y, Sodroski J, Finzi A. 2013. The highly conserved layer-3 component of the HIV-1 gp120 inner domain is critical for CD4-required conformational transitionsJ Virol87:2549–2562. doi:10.1128/JVI.03104-12. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  11. Finzi A, Pacheco B, Xiang SH, Pancera M, Herschhorn A, Wang L, Zeng X, Desormeaux A, Kwong PD, Sodroski J. 2012. Lineage-specific differences between human and simian immunodeficiency virus regulation of gp120 trimer association and CD4 bindingJ Virol86:8974–8986. doi:10.1128/JVI.01076-12. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  12. Li H, Wang S, Kong R, Ding W, Lee FH, Parker Z, Kim E, Learn GH, Hahn P, Policicchio B, Brocca-Cofano E, Deleage C, Hao X, Chuang GY, Gorman J, Gardner M, Lewis MG, Hatziioannou T, Santra S, Apetrei C, Pandrea I, Alam SM, Liao HX, Shen X, Tomaras GD, Farzan M, Chertova E, Keele BF, Estes JD, Lifson JD, Doms RW, Montefiori DC, Haynes BF, Sodroski JG, Kwong PD, Hahn BH, Shaw GM. 2016. Envelope residue 375 substitutions in simian-human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaquesProc Natl Acad Sci U S A113:E3413–E3422. doi:10.1073/pnas.1606636113. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  13. Veillette M, Coutu M, Richard J, Batraville LA, Dagher O, Bernard N, Tremblay C, Kaufmann DE, Roger M, Finzi A. 2015. The HIV-1 gp120 CD4-bound conformation is preferentially targeted by antibody-dependent cellular cytotoxicity-mediating antibodies in sera from HIV-1-infected individualsJ Virol89:545–551. doi:10.1128/JVI.02868-14. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  14. Veillette M, Desormeaux A, Medjahed H, Gharsallah NE, Coutu M, Baalwa J, Guan Y, Lewis G, Ferrari G, Hahn BH, Haynes BF, Robinson JE, Kaufmann DE, Bonsignori M, Sodroski J, Finzi A. 2014. Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicityJ Virol88:2633–2644. doi:10.1128/JVI.03230-13. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  15. Arias JF, Heyer LN, von Bredow B, Weisgrau KL, Moldt B, Burton DR, Rakasz EG, Evans DT. 2014. Tetherin antagonism by Vpu protects HIV-infected cells from antibody-dependent cell-mediated cytotoxicityProc Natl Acad Sci U S A111:6425–6430. doi:10.1073/pnas.1321507111. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  16. Alvarez RA, Hamlin RE, Monroe A, Moldt B, Hotta MT, Rodriguez Caprio G, Fierer DS, Simon V, Chen BK. 2014. HIV-1 Vpu antagonism of tetherin inhibits antibody-dependent cellular cytotoxic responses by natural killer cellsJ Virol88:6031–6046. doi:10.1128/JVI.00449-14. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  17. von Bredow B, Arias JF, Heyer LN, Gardner MR, Farzan M, Rakasz EG, Evans DT. 12 August 2015. Envelope glycoprotein internalization protects human and simian immunodeficiency virus infected cells from antibody-dependent cell-mediated cytotoxicityJ Viroldoi:10.1128/JVI.01911-15. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  18. Richard J, Veillette M, Brassard N, Iyer SS, Roger M, Martin L, Pazgier M, Schon A, Freire E, Routy JP, Smith AB III, Park J, Jones DM, Courter JR, Melillo BN, Kaufmann DE, Hahn BH, Permar SR, Haynes BF, Madani N, Sodroski JG, Finzi A. 2015. CD4 mimetics sensitize HIV-1-infected cells to ADCCProc Natl Acad Sci U S A112:E2687–E2694. doi:10.1073/pnas.1506755112. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  19. Lee WS, Richard J, Lichtfuss M, Smith AB III, Park J, Courter JR, Melillo BN, Sodroski JG, Kaufmann DE, Finzi A, Parsons MS, Kent SJ. 2015. Antibody-dependent cellular cytotoxicity against reactivated HIV-1-infected cellsJ Virol90:2021–2030. doi:10.1128/JVI.02717-15. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  20. Richard J, Pacheco B, Gohain N, Veillette M, Ding S, Alsahafi N, Tolbert WD, Prevost J, Chapleau JP, Coutu M, Jia M, Brassard N, Park J, Courter JR, Melillo B, Martin L, Tremblay C, Hahn BH, Kaufmann DE, Wu X, Smith AB III, Sodroski J, Pazgier M, Finzi A. 9 September 2016. Co-receptor binding site antibodies enable CD4-mimetics to expose conserved anti-cluster A ADCC epitopes on HIV-1 envelope glycoproteinsEBioMedicinedoi:10.1016/j.ebiom.2016.09.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  21. Richard J, Veillette M, Batraville LA, Coutu M, Chapleau JP, Bonsignori M, Bernard N, Tremblay C, Roger M, Kaufmann DE, Finzi A. 2014. Flow cytometry-based assay to study HIV-1 gp120 specific antibody-dependent cellular cytotoxicity responsesJ Virol Methods208:107–114. doi:10.1016/j.jviromet.2014.08.003. [PubMed] [CrossRef] [Google Scholar]
  22. Ding S, Veillette M, Coutu M, Prevost J, Scharf L, Bjorkman PJ, Ferrari G, Robinson JE, Sturzel C, Hahn BH, Sauter D, Kirchhoff F, Lewis GK, Pazgier M, Finzi A. 2016. A highly conserved residue of the HIV-1 gp120 inner domain is important for antibody-dependent cellular cytotoxicity responses mediated by anti-cluster A antibodiesJ Virol90:2127–2134. doi:10.1128/JVI.02779-15. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  23. Tolbert WD, Gohain N, Veillette M, Chapleau JP, Orlandi C, Visciano ML, Ebadi M, DeVico AL, Fouts TR, Finzi A, Lewis GK, Pazgier M. 2016. Paring down HIV Env: design and crystal structure of a stabilized inner domain of HIV-1 gp120 displaying a major ADCC target of the A32 regionStructure24:697–709. doi:10.1016/j.str.2016.03.005. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  24. Guan Y, Pazgier M, Sajadi MM, Kamin-Lewis R, Al-Darmarki S, Flinko R, Lovo E, Wu X, Robinson JE, Seaman MS, Fouts TR, Gallo RC, DeVico AL, Lewis GK. 2013. Diverse specificity and effector function among human antibodies to HIV-1 envelope glycoprotein epitopes exposed by CD4 bindingProc Natl Acad Sci U S A110:E69–E78. doi:10.1073/pnas.1217609110. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  25. Ferrari G, Pollara J, Kozink D, Harms T, Drinker M, Freel S, Moody MA, Alam SM, Tomaras GD, Ochsenbauer C, Kappes JC, Shaw GM, Hoxie JA, Robinson JE, Haynes BF. 2011. An HIV-1 gp120 envelope human monoclonal antibody that recognizes a C1 conformational epitope mediates potent antibody-dependent cellular cytotoxicity (ADCC) activity and defines a common ADCC epitope in human HIV-1 serumJ Virol85:7029–7036. doi:10.1128/JVI.00171-11. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  26. Bonsignori M, Pollara J, Moody MA, Alpert MD, Chen X, Hwang KK, Gilbert PB, Huang Y, Gurley TC, Kozink DM, Marshall DJ, Whitesides JF, Tsao CY, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Kim JH, Michael NL, Tomaras GD, Montefiori DC, Lewis GK, Devico A, Evans DT, Ferrari G, Liao HX, Haynes BF. 2012. Antibody-dependent cellular cytotoxicity-mediating antibodies from an HIV-1 vaccine efficacy trial target multiple epitopes and preferentially use the VH1 gene familyJ Virol86:11521–11532. doi:10.1128/JVI.01023-12. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  27. Zoubchenok D, Veillette M, Prevost J, Sanders-Buell E, Wagh K, Korber B, Chenine AL, Finzi A. 7 December 2016. Histidine 375 modulates CD4 binding in HIV-1 CRF01_AE envelope glycoproteinsJ Viroldoi:10.1128/JVI.02151-16. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  28. Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, Evans DT, Montefiori DC, Karnasuta C, Sutthent R, Liao HX, DeVico AL, Lewis GK, Williams C, Pinter A, Fong Y, Janes H, DeCamp A, Huang Y, Rao M, Billings E, Karasavvas N, Robb ML, Ngauy V, de Souza MS, Paris R, Ferrari G, Bailer RT, Soderberg KA, Andrews C, Berman PW, Frahm N, De Rosa SC, Alpert MD, Yates NL, Shen X, Koup RA, Pitisuttithum P, Kaewkungwal J, Nitayaphan S, Rerks-Ngarm S, Michael NL, Kim JH. 2012. Immune-correlates analysis of an HIV-1 vaccine efficacy trialN Engl J Med366:1275–1286. doi:10.1056/NEJMoa1113425. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  29. McCutchan FE. 2006. Global epidemiology of HIVJ Med Virol78(Suppl 1):S7–S12. doi:10.1002/jmv.20599. [PubMed] [CrossRef] [Google Scholar]
  30. Burke DS. 1997. Recombination in HIV: an important viral evolutionary strategyEmerg Infect Dis3:253–259. doi:10.3201/eid0303.970301. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  31. Taylor BS, Hammer SM. 2008. The challenge of HIV-1 subtype diversityN Engl J Med359:1965–1966. doi:10.1056/NEJMc086373. [PubMed] [CrossRef] [Google Scholar]
  32. Hemelaar J. 2012. The origin and diversity of the HIV-1 pandemicTrends Mol Med18:182–192. doi:10.1016/j.molmed.2011.12.001. [PubMed] [CrossRef] [Google Scholar]
  33. Hemelaar J. 2013. Implications of HIV diversity for the HIV-1 pandemicJ Infect66:391–400. doi:10.1016/j.jinf.2012.10.026. [PubMed] [CrossRef] [Google Scholar]
  34. Veillette M, Coutu M, Richard J, Batraville LA, Desormeaux A, Roger M, Finzi A. 14 September 2014. Conformational evaluation of HIV-1 trimeric envelope glycoproteins using a cell-based ELISA assayJ Vis Expdoi:10.3791/51995. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  35. Veillette M, Richard J, Pazgier M, Lewis GK, Parsons MS, Finzi A. 2016. Role of HIV-1 envelope glycoproteins conformation and accessory proteins on ADCC responsesCurr HIV Res14:9–23. [PubMed] [Google Scholar]
  36. Schader SM, Colby-Germinario SP, Quashie PK, Oliveira M, Ibanescu RI, Moisi D, Mesplede T, Wainberg MA. 2012. HIV gp120 H375 is unique to HIV-1 subtype CRF01_AE and confers strong resistance to the entry inhibitor BMS-599793, a candidate microbicide drugAntimicrob Agents Chemother56:4257–4267. doi:10.1128/AAC.00639-12. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  37. Richard J, Veillette M, Ding S, Zoubchenok D, Alsahafi N, Coutu M, Brassard N, Park J, Courter JR, Melillo B, Smith AB III, Shaw GM, Hahn BH, Sodroski J, Kaufmann DE, Finzi A. 2016. Small CD4 mimetics prevent HIV-1 uninfected bystander CD4+ T cell killing mediated by antibody-dependent cell-mediated cytotoxicityEBioMedicine3:122–134. doi:10.1016/j.ebiom.2015.12.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  38. Liao HX, Bonsignori M, Alam SM, McLellan JS, Tomaras GD, Moody MA, Kozink DM, Hwang KK, Chen X, Tsao CY, Liu P, Lu X, Parks RJ, Montefiori DC, Ferrari G, Pollara J, Rao M, Peachman KK, Santra S, Letvin NL, Karasavvas N, Yang ZY, Dai K, Pancera M, Gorman J, Wiehe K, Nicely NI, Rerks-Ngarm S, Nitayaphan S, Kaewkungwal J, Pitisuttithum P, Tartaglia J, Sinangil F, Kim JH, Michael NL, Kepler TB, Kwong PD, Mascola JR, Nabel GJ, Pinter A, Zolla-Pazner S, Haynes BF. 2013. Vaccine induction of antibodies against a structurally heterogeneous site of immune pressure within HIV-1 envelope protein variable regions 1 and 2Immunity38:176–186. doi:10.1016/j.immuni.2012.11.011. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  39. Sun Y, Asmal M, Lane S, Permar SR, Schmidt SD, Mascola JR, Letvin NL. 2011. Antibody-dependent cell-mediated cytotoxicity in simian immunodeficiency virus-infected rhesus monkeysJ Virol85:6906–6912. doi:10.1128/JVI.00326-11. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  40. Banks ND, Kinsey N, Clements J, Hildreth JE. 2002. Sustained antibody-dependent cell-mediated cytotoxicity (ADCC) in SIV-infected macaques correlates with delayed progression to AIDSAIDS Res Hum Retroviruses18:1197–1205. doi:10.1089/08892220260387940. [PubMed] [CrossRef] [Google Scholar]
  41. Alpert MD, Harvey JD, Lauer WA, Reeves RK, Piatak M Jr, Carville A, Mansfield KG, Lifson JD, Li W, Desrosiers RC, Johnson RP, Evans DT. 2012. ADCC develops over time during persistent infection with live-attenuated SIV and is associated with complete protection against SIV(mac)251 challengePLoS Pathog8:e1002890. doi:10.1371/journal.ppat.1002890. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  42. Baum LL, Cassutt KJ, Knigge K, Khattri R, Margolick J, Rinaldo C, Kleeberger CA, Nishanian P, Henrard DR, Phair J. 1996. HIV-1 gp120-specific antibody-dependent cell-mediated cytotoxicity correlates with rate of disease progressionJ Immunol157:2168–2173. [PubMed] [Google Scholar]
  43. Forthal DN, Landucci G, Haubrich R, Keenan B, Kuppermann BD, Tilles JG, Kaplan J. 1999. Antibody-dependent cellular cytotoxicity independently predicts survival in severely immunocompromised human immunodeficiency virus-infected patientsJ Infect Dis180:1338–1341. doi:10.1086/314988. [PubMed] [CrossRef] [Google Scholar]
  44. Ljunggren K, Moschese V, Broliden PA, Giaquinto C, Quinti I, Fenyo EM, Wahren B, Rossi P, Jondal M. 1990. Antibodies mediating cellular cytotoxicity and neutralization correlate with a better clinical stage in children born to human immunodeficiency virus-infected mothersJ Infect Dis161:198–202. doi:10.1093/infdis/161.2.198. [PubMed] [CrossRef] [Google Scholar]
  45. Chung AW, Navis M, Isitman G, Wren L, Silvers J, Amin J, Kent SJ, Stratov I. 2011. Activation of NK cells by ADCC antibodies and HIV disease progressionJ Acquir Immune Defic Syndr58:127–131. doi:10.1097/QAI.0b013e31822c62b9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  46. Mabuka J, Nduati R, Odem-Davis K, Peterson D, Overbaugh J. 2012. HIV-specific antibodies capable of ADCC are common in breastmilk and are associated with reduced risk of transmission in women with high viral loadsPLoS Pathog8:e1002739. doi:10.1371/journal.ppat.1002739. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  47. Tomaras GD, Ferrari G, Shen X, Alam SM, Liao HX, Pollara J, Bonsignori M, Moody MA, Fong Y, Chen X, Poling B, Nicholson CO, Zhang R, Lu X, Parks R, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Gilbert PB, Kim JH, Michael NL, Montefiori DC, Haynes BF. 9 May 2013. Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgGProc Natl Acad Sci U S Adoi:10.1073/pnas.1301456110. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  48. Li X, Li W, Zhong P, Fang K, Zhu K, Musa TH, Song Y, Du G, Gao R, Guo Y, Yan W, Xuan Y, Wei P. 16 June 2016. Nationwide trends in molecular epidemiology of HIV-1 in ChinaAIDS Res Hum Retrovirusesdoi:10.1089/AID.2016.0029. [PubMed] [CrossRef] [Google Scholar]
  49. Zhong P, Pan Q, Ning Z, Xue Y, Gong J, Zhen X, Zhou L, Sheng F, Zhang W, Gai J, Cheng H, Yue Q, Xing H, Zhuang M, Lu W, Shao Y, Kang L. 2007. Genetic diversity and drug resistance of human immunodeficiency virus type 1 (HIV-1) strains circulating in ShanghaiAIDS Res Hum Retroviruses23:847–856. doi:10.1089/aid.2006.0196. [PubMed] [CrossRef] [Google Scholar]
  50. He X, Xing H, Ruan Y, Hong K, Cheng C, Hu Y, Xin R, Wei J, Feng Y, Hsi JH, Takebe Y, Shao Y., Group for HIV Molecular Epidemiology Survey. 2012. A comprehensive mapping of HIV-1 genotypes in various risk groups and regions across China based on a nationwide molecular epidemiologic surveyPLoS One7:e47289. doi:10.1371/journal.pone.0047289. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  51. Hu DJ, Vanichseni S, Mastro TD, Raktham S, Young NL, Mock PA, Subbarao S, Parekh BS, Srisuwanvilai L, Sutthent R, Wasi C, Heneine W, Choopanya K. 2001. Viral load differences in early infection with two HIV-1 subtypesAIDS15:683–691. doi:10.1097/00002030-200104130-00003. [PubMed] [CrossRef] [Google Scholar]
  52. Rangsin R, Piyaraj P, Sirisanthana T, Sirisopana N, Short O, Nelson KE. 2007. The natural history of HIV-1 subtype E infection in young men in Thailand with up to 14 years of follow-upAIDS21(Suppl 6):S39–S46. doi:10.1097/01.aids.0000299409.29528.23. [PubMed] [CrossRef] [Google Scholar]
  53. Rangsin R, Chiu J, Khamboonruang C, Sirisopana N, Eiumtrakul S, Brown AE, Robb M, Beyrer C, Ruangyuttikarn C, Markowitz LE, Nelson KE. 2004. The natural history of HIV-1 infection in young Thai men after seroconversionJ Acquir Immune Defic Syndr36:622–629. doi:10.1097/00126334-200405010-00011. [PubMed] [CrossRef] [Google Scholar]
  54. Robinson JE, Holton D, Elliott S, Ho DD. 1992. Distinct antigenic sites on HIV gp120 identified by a panel of human monoclonal antibodiesJ Cell Biochem Suppl16E:Q449. [Google Scholar]
  55. Zhang W, Godillot AP, Wyatt R, Sodroski J, Chaiken I. 2001. Antibody 17b binding at the coreceptor site weakens the kinetics of the interaction of envelope glycoprotein gp120 with CD4Biochemistry40:1662–1670. doi:10.1021/bi001397m. [PubMed] [CrossRef] [Google Scholar]
  56. Fontaine J, Chagnon-Choquet J, Valcke HS, Poudrier J, Roger M., Montreal Primary HIV Infection and Long-Term Non-Progressor Study Groups. 2011. High expression levels of B lymphocyte stimulator (BLyS) by dendritic cells correlate with HIV-related B-cell disease progression in humansBlood117:145–155. doi:10.1182/blood-2010-08-301887. [PubMed] [CrossRef] [Google Scholar]
  57. Fontaine J, Coutlee F, Tremblay C, Routy JP, Poudrier J, Roger M., Montreal Primary HIV Infection and Long-Term Nonprogressor Study Groups. 2009. HIV infection affects blood myeloid dendritic cells after successful therapy and despite nonprogressing clinical diseaseJ Infect Dis199:1007–1018. doi:10.1086/597278. [PubMed] [CrossRef] [Google Scholar]
  58. Peretz Y, Ndongala ML, Boulet S, Boulassel MR, Rouleau D, Cote P, Longpre D, Routy JP, Falutz J, Tremblay C, Tsoukas CM, Sekaly RP, Bernard NF. 2007. Functional T cell subsets contribute differentially to HIV peptide-specific responses within infected individuals: correlation of these functional T cell subsets with markers of disease progressionClin Immunol124:57–68. doi:10.1016/j.clim.2007.04.004. [PubMed] [CrossRef] [Google Scholar]
  59. Kamya P, Boulet S, Tsoukas CM, Routy JP, Thomas R, Cote P, Boulassel MR, Baril JG, Kovacs C, Migueles SA, Connors M, Suscovich TJ, Brander C, Tremblay CL, Bernard N., Canadian Cohort of HIV Infected Slow Progressors. 2011. Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57J Virol85:5949–5960. doi:10.1128/JVI.02652-10. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  60. International HIV Controllers Study, Pereyra F, Jia X, McLaren PJ, Telenti A, de Bakker PI, Walker BD, Ripke S, Brumme CJ, Pulit SL, Carrington M, Kadie CM, Carlson JM, Heckerman D, Graham RR, Plenge RM, Deeks SG, Gianniny L, Crawford G, Sullivan J, Gonzalez E, Davies L, Camargo A, Moore JM, Beattie N, Gupta S, Crenshaw A, Burtt NP, Guiducci C, Gupta N, Gao X, Qi Y, Yuki Y, Piechocka-Trocha A, Cutrell E, Rosenberg R, Moss KL, Lemay P, O'Leary J, Schaefer T, Verma P, Toth I, Block B, Baker B, Rothchild A, Lian J, Proudfoot J, Alvino DM, Vine S, Addo MM, et al. 2010. The major genetic determinants of HIV-1 control affect HLA class I peptide presentationScience330:1551–1557. doi:10.1126/science.1195271. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
  61. Bunupuradah T, Chetchotisakd P, Ananworanich J, Munsakul W, Jirajariyavej S, Kantipong P, Prasithsirikul W, Sungkanuparph S, Bowonwatanuwong C, Klinbuayaem V, Kerr SJ, Sophonphan J, Bhakeecheep S, Hirschel B, Ruxrungtham K., HIV STAR Study Group. 2012. A randomized comparison of second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir in patients failing NNRTI regimens: the HIV STAR studyAntivir Ther17:1351–1361. doi:10.3851/IMP2443. [PubMed] [CrossRef] [Google Scholar]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

 

Jawahar Raina

Leave a comment

Please note: comments must be approved before they are published.