Association of HIV-1 Gag-Specific IgG Antibodies With Natural Control of HIV-1 Infection in Individuals Not Carrying HLA-B*57:01 Is Only Observed in Viremic Controllers : JAIDS Journal of Acquired Immune Deficiency Syndromes

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Association of HIV-1 Gag-Specific IgG Antibodies With Natural Control of HIV-1 Infection in Individuals Not Carrying HLA-B*57:01 Is Only Observed in Viremic Controllers

Tjiam, M. Christian BMedSc(Hons)*; Morshidi, Mazmah A. MInfectDis*; Sariputra, Lucy MInfectDis*; Martin, Jeffrey N. MD, MPH†; Deeks, Steven G. MD‡; Tan, Dino B. A. PhD§; Lee, Silvia PhD‖,¶; Fernandez, Sonia PhD*; French, Martyn A. MD*,#,**

Author Information

*School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia

†Division of Clinical Epidemiology, University of California, San Francisco, CA

‡School of Medicine, University of California, San Francisco, CA

§Stem Cell Unit, Institute of Respiratory Health, Perth, Western Australia, Australia

‖Department of Microbiology and Infectious Diseases, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Western Australia, Australia

School of Biomedical Sciences, Curtin University, Perth, Western Australia, Australia

#Medical School, University of Western Australia, Perth, Western Australia, Australia

**Department of Clinical Immunology, Royal Perth Hospital and PathWest Laboratory Medicine, Perth, Western Australia, Australia

Supported by the National Health and Medical Research Council of Australia (grant 510448) and the Medical Research Foundation of Royal Perth Hospital (grant 2011/027). S.F. was supported by a fellowship from the Royal Perth Hospital Medical Research Foundation. The University of California San Francisco SCOPE cohort was supported by the Delaney AIDS Research Enterprise (grant AI096109), the University of California San Francisco/Gladstone Institute of Virology and Immunology Center for AIDS Research (grant P30 AI027763), and by the Center for AIDS Research Network of Integrated Systems (grant R24 AI067039).

The authors have no funding or conflicts of interest to disclose.

The manuscript was written by M.A.F., M.C.T., and S.F. Laboratory work was performed by M.C.T., M.A.M., L.S., S.L., S.F., and D.B.A.T. Data analyses were performed by M.C.T. Patient plasma samples were provided by S.G.D. and J.N.M. All authors reviewed and provided comment on the manuscript.

JAIDS Journal of Acquired Immune Deficiency Syndromes 76(3):p e90-e92, November 1, 2017. | DOI: 10.1097/QAI.0000000000001477
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To the Editors:

Defining immune responses that naturally control HIV-1 infection will enlighten therapeutic HIV-1 vaccine design. It is well established that CD8+ T-cell responses against peptides of HIV-1 capsid proteins encoded by gag (Gag proteins) and carriage of “protective” alleles of genes for human leukocyte antigen (HLA)-B molecules, which present peptides of HIV-1 Gag proteins to CD8+ T cells, correlate with immune control of HIV-1 infection.1–3 In individuals of European descent, the most “protective” allele of HLA-B is HLA-B*57:01,3 which encodes HLA molecules that bind fewer self-peptides and exhibit greater cross-reactive binding of viral peptides than other HLA-B alleles, contributing to exceptional long-term control of HIV-1 replication in carriers.4 However, approximately 30%–40% of individuals who naturally control HIV-1 infection (HIV controllers) do not possess a “protective” HLA-B allele,1,2 suggesting that immune responses other than those mediated by CD8+ T cells contribute to immune control of HIV-1 infection. Recently, Koofhethile et al5 demonstrated that viremic controllers (VCs) not carrying “protective” alleles of HLA-B genes control HIV-1 infection more robustly than carriers and that CD8+ T cells do not mediate this effect. In addition, Freund et al6 demonstrated that HIV-1 Env-specific antibodies with broad neutralizing activity might have contributed to long-term control of HIV-1 infection in an elite controller (EC), who carried the “protective” HLA-B alleles HLA-B*57:01 and HLA-B*27:05. However, the findings of previous studies on the role of antibodies in the natural control of HIV-1 infection have been inconclusive.2,7–11

We have previously provided evidence that HIV-1 Gag-specific IgG antibodies might contribute to the control of HIV-1 infection,12–15 including in HIV controllers not carrying HLA-B*57:01,13 and proposed that these antibodies mediate HIV-1 Gag-specific plasmacytoid dendritic cell–reactive opsonophagocytic antibody (PROAb) responses.14 Importantly, in analyzing the relationship between HIV-1 Gag-specific IgG antibodies and “protective” HLA-B alleles in our previous study,13 we did not differentiate between VCs and ECs. We have therefore undertaken this analysis for the patients reported in Tjiam et al.14 As both IgG1 and IgG2 antibodies contribute to opsonophagocytic antibody responses that activate dendritic cells through FcγRIIa,16 we examined HIV-1 p24-specific IgG1 and IgG2 antibody levels and HIV-1 p24-specific PROAb responses in the previously reported VCs (n = 29) and ECs (n = 30),14 stratifying them into subgroups based on carriage, or not, of HLA-B*57:01 or other “protective” HLA-B alleles (HLA-B*14:02, 27:05, 52:01, 58:01, and 81:01) defined in European and African patients.3,5 Noncontrollers (NCs; n = 30) were included for comparison.

As shown in Figure 1, HIV-1 p24-specific IgG1 and IgG2 antibodies were higher in VCs than in NCs, except for VCs carrying HLA-B*57:01 (Figs. 1A, B). HIV-1 p24-specific PROAb responses were also higher in VCs than in NCs, but a relationship with “protective” HLA-B alleles was not apparent (Fig. 1C). In contrast, ECs exhibited essentially no differences in HIV-1 p24-specific IgG antibodies when compared with NCs (Figs. 1D–F). We also examined the relationship between HIV-1 gp140-specific IgG1 and IgG2 antibody levels demonstrated in these patients,14 with “protective” HLA-B alleles (Figs. 1G–J). HIV-1 gp140-specific IgG2 antibodies exhibited a relationship with HLA-B*57:01 that was similar to HIV-1 p24-specific IgG2 antibodies but in ECs rather than in VCs (Fig. 1J). In VCs, HIV-1 gp140-specific IgG1 antibodies were higher in patients carrying HLA-B*57:01 (Fig. 1G).

F1
FIGURE 1.:
Based on plasma HIV-1 RNA levels, antiretroviral-naive HIV-1–infected individuals were classified as ECs (<75 copies/mL), VCs (75–2000 copies/mL), or NCs (>10,000 copies/mL). VCs and ECs were subgrouped based on possession of HLA-B*57:01, other “protective” HLA-B alleles (HLA-B*14:02, B*27:05, B*52:01, B*58:01, and B*81:01), or no “protective” HLA-B alleles. HIV NCs were included for comparison. Within VCs, differences in IgG antibody responses against HIV-1 p24 (A–C) and HIV-1 gp140 (G and H) between subgroups are shown. Within ECs, differences in IgG antibody responses against HIV-1 p24 (D–F) and HIV-1 gp140 (I and J) between subgroups are shown. Differences between subgroups were compared using Mann–Whitney tests (*P ≤ 0.05, **P < 0.01, ***P < 0.001, ns = P > 0.05).

These findings expand on our previous findings13 by demonstrating that the association between HIV-1 p24-specific IgG antibodies and natural control of HIV-1 infection in individuals not carrying HLA-B*57:01 is only observed in VCs. This observation was made for HIV-1 p24-specific IgG1 and IgG2 antibodies but not for PROAb responses, possibly because they are detected by a functional antibody assay that may be affected by factors other than binding of antibodies with antigens in an enzyme immunoassay. Furthermore, our findings provide more evidence that IgG2 antibodies to HIV-1 Env antigens are associated with control of HIV-1 infection,10,17 but only in ECs not carrying HLA-B*57:01. We suggest that HIV-1 p24-specific IgG1 and IgG2 antibodies, possibly including PROAb responses, might contribute to non–CD8+ T cell–mediated control of HIV-1 infection in patients with low-level HIV-1 replication5 and that this requires further investigation. We also suggest that these investigations should consider the possibility that HIV-1 Gag-specific IgG antibodies mediate an antibody response against HIV-1 capsids extracellularly through PROAb responses mediated through FcγRIIa14 and/or intracellularly through the neonatal Fc receptor and the cytosolic Fc receptor TRIM21/Ro52.18,19 The former type of antibody response has been associated with immune control of non-enveloped RNA viruses,20–22 where antibody-mediated opsonization of virions leads to their phagocytosis by plasmacytoid dendritic cells and interferon-α production through viral RNA binding to TLR7, and also with control of enveloped influenza viruses by a similar mechanism in mouse models of influenza virus disease.23 We also demonstrated that carriage of HLA-B*57:01 was associated with HIV-1 gp140-specific antibody levels in HIV controllers but in contrast to HIV-1 p24-specific antibodies, the patterns of association were inconsistent. Thus, HIV-1 gp140-specific IgG1 antibody levels were higher in VCs carrying HLA-B*57:01, whereas IgG2 antibody levels were higher in ECs not carrying HLA-B*57:01. Although it was notable that lack of HLA-B*57:01 carriage was associated with higher HIV-1 gp140-specific IgG2 antibodies in ECs and higher HIV-1 p24-specific IgG1 and IgG2 antibodies in VCs, it was not possible to determine whether gp140-specific IgG2 antibodies in ECs correlated negatively with HIV viral load, as was shown for HIV-1 p24 IgG antibodies in patients with viremia.14

In conclusion, our findings highlight the importance of examining patients with active HIV-1 replication, and considering the exceptional effects of HLA-B*57:01 on control of HIV-1 infection, when investigating the role of HIV-1 Gag-specific IgG antibodies in controlling HIV-1 infection.

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