CD8 ⁺ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

Abstract

The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P ‫؍‬ 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8 ؉ T cell responses against Gag and enhanced ability of CD8 ؉ T cells to suppress viral replication ex vivo. In some cases, loss of virological control was associated with reduction in the total breadth of CD8 ؉ T cell responses in the absence of differences in HIV-1-specific CD8 ؉ T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8 ؉ T cell responses characterized by reduced ability to suppress viral replication ex vivo. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8 ؉ T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8 ؉ T cell-independent mechanisms. H IV remains a global problem, and sub-Saharan Africa continues to bear the brunt of the epidemic, accounting for 67% of the infected people worldwide (1). Understanding the mechanisms of natural viral control in HIV infection is crucial for the identification of correlates of immune protection and for the design of an effective HIV vaccine. Previous studies have linked HIV control to a number of immunological factors, particularly HIVspecific CD8 ϩ cytotoxic T lymphocytes (CTLs), which have been demonstrated to play an important role (2-5). However, virusspecific CD8 ϩ T cell immune responses are not equally effective in HIV control, as the majority of infected individuals progress to disease despite the presence of these cells. HIV is able to evade immune responses by developing mutations that mediate escape from CTL recognition (6-12). In addition, the expression of certain HLA class I molecules by HIV-infected patients, such as HLA-B*27, HLA-B*57, HLA-B*58:01, HLA-B*81:01, and HLA-A*74: 01, is associated with better clinical disease outcomes in some population settings (3,(13)(14)(15)(16)(17)(18). HLA class I proteins present viral peptides on the surface of antigen-presenting cells to CTLs, and a major mechanism by which these protective alleles slow HIV disease progression is believed to be through CTL activity (18).

Factors Leading to the Loss of Natural Elite Control of HIV-1 Infection

“…(D) Using logistic regression and receiver operator characteristic (ROC) curves, we assessed three different multimarker models that could accurately predict the loss of control in EC: model A (blue), which includes the statistically significant variables in the Mann-Whitney U test, model B (green), composed of the top five variables obtained from the random forest analysis, and model C (orange), compounded by the two variables obtained in the PCA analysis. agreement with a previous work showing a decreased CD8 ϩ T-cell breadth that was associated with loss of viral control but in viremic controllers, although we did not observe an association between functional Gag-specific CD8 ϩ T cells and the presence of protective HLA class I alleles (28). One possible mechanism involved in the loss of control may be related to the fact that CD8 ϩ T cells restricted by "nonprotective" HLA allele groups can be suppressed by regulatory T cells (29).…”

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

“…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 al [5] 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 al [6] demonstrated that HIV-1 Env-specific antibodies with broad neutralising 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.…”

“…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 via 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]. Non-controllers (NCs; n=30) were included for comparison.…”

“…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 replication [5] 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 via PROAb responses mediated through FcγRIIa [14] and/or intracellularly via the neonatal Fc receptor and the cytosolic Fc receptor TRIM21/Ro52 [18, 19].…”

Dual HLA B*42 and B*81-reactive T cell receptors recognize more diverse HIV-1 Gag escape variants

“…Following infection with HIV-1 subtype C strains that are prevalent in sub-Saharan Africa, expression of HLA allele B*81:01 is associated with improved clinical outcomes 9 , 31 , while the genetically-related allele B*42:01 is less protective 16 , 31 – 36 . Both alleles belong to the HLA B7 supertype 37 , 38 and present similar viral peptides, including the immunodominant p24 Gag epitope TL9 (TPQDLNTML 180–188 ) 34 , 39 – 42 .…”