Impact of HLA in Mother and Child on Disease Progression of Pediatric Human Immunodeficiency Virus Type 1 Infection

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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).

Section: Discussionsupporting

confidence: 53%

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

Koofhethile

Ndhlovu

Thobakgale-Tshabalala

et al. 2016

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“…Protective alleles were defined as those that were most strongly associated with lower viral loads in HIV-1 subtype C-infected individuals, namely, HLA-B*57, HLA-B*5801, and HLA- (20), and were also found later to be the most strongly associated with lower viral loads or higher CD4 counts in a cohort of over 1,000 HIV-1 subtype C-infected individuals (43). The proportion of individuals possessing a protective allele was significantly greater in the low-replication-capacity group than in the high-replication-capacity group (Fisher's exact test; P ϭ 0.003) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The magnitude and/or breadth of HLA-restricted CTL responses to the conserved Gag protein has been correlated inversely with disease progression or markers of disease progression in several studies (12,21,28,31,35,43,46), although there are some exceptions (4,16,37), while preferential targeting of the highly variable envelope protein (as occurs in HLA-B*5802-positive individuals) correlates with higher viral loads (21,29). Protective HLA alleles restrict CTL responses that impose a strong selection pressure on a few specific Gag p24 epitopes, resulting in escape mutations (14) for which fitness costs have been demonstrated either through site-directed mutations introduced into a reference strain background (2,8,25,38) or through in vivo reversion of these mutations after transmission to an HLA-mismatched individ-ual (8,24).…”

mentioning

confidence: 99%

Gag-Protease-Mediated Replication Capacity in HIV-1 Subtype C Chronic Infection: Associations with HLA Type and Clinical Parameters

Wright

Brumme

Carlson

et al. 2010

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176

The mechanisms underlying HIV-1 control by protective HLA class I alleles are not fully understood and could involve selection of escape mutations in functionally important Gag epitopes resulting in fitness costs. This study was undertaken to investigate, at the population level, the impact of HLA-mediated immune pressure in Gag on viral fitness and its influence on HIV-1 pathogenesis. Replication capacities of 406 recombinant viruses encoding plasma-derived Gag-protease from patients chronically infected with HIV-1 subtype C were assayed in an HIV-1-inducible green fluorescent protein reporter cell line. Viral replication capacities varied significantly with respect to the specific HLA-B alleles expressed by the patient, and protective HLA-B alleles, most notably HLA-B*81, were associated with lower replication capacities. HLA-associated mutations at low-entropy sites, especially the HLA-B*81-associated 186S mutation in the TL9 epitope, were associated with lower replication capacities. Most mutations linked to alterations in replication capacity in the conserved p24 region decreased replication capacity, while most in the highly variable p17 region increased replication capacity. Replication capacity also correlated positively with baseline viral load and negatively with baseline CD4 count but did not correlate with the subsequent rate of CD4 decline. In conclusion, there is evidence that protective HLA alleles, in particular HLA-B*81, significantly influence Gag-protease function by driving sequence changes in Gag and that conserved regions of Gag should be included in a vaccine aiming to drive HIV-1 toward a less fit state. However, the long-term clinical benefit of immune-driven fitness costs is uncertain given the lack of correlation with longitudinal markers of disease progression.

“…Evidence for favorable or unfavorable relationships of certain HLA-I markers to virologic and immunologic outcomes of HIV infection is conclusive (19,27,28,33,35,(37)(38)(39). Here we evaluated a set of these markers chosen on the basis of their documented impact and population frequencies in this Zambian HIV-discordant heterosexual transmission cohort.…”

Section: Study Population and Virus Phylogenymentioning

confidence: 99%

“…Gender has also been observed to modulate VL in both early and chronic infections in antiretroviral-naïve and -treated populations (29-31), although the exact mechanism for this is not known (32). Finally, sharing of HLA-I alleles between the TSP and the SC can lead to reduced control of virus following transmission because of the existence of CTL escape mutations selected in the TSP that reduce the efficacy of the de novo immune response (11,19,33). In our current study of 195 phylogenetically linked heterosexual transmission couples, we had a sufficiently large population to document for the first time that while the phenotype of the transmitted founder virus had a significant impact on early set-point VL, the gender of the SC as well as the immunogenetic characteristics of both the TSP and the SC significantly and independently modulated this effect.…”

mentioning

confidence: 99%

Cumulative Impact of Host and Viral Factors on HIV-1 Viral-Load Control during Early Infection

Yue

Prentice

Farmer

et al. 2013

fIn HIV-1 infection, the early set-point viral load strongly predicts both viral transmission and disease progression. The factors responsible for the wide spectrum of set-point viral loads are complex and likely reflect an interplay between the transmitted virus and genetically defined factors in both the transmitting source partner and the seroconverter. Indeed, analysis of 195 transmission pairs from Lusaka, Zambia, revealed that the viral loads in transmitting source partners contributed only ϳ2% of the variance in early set-point viral loads of seroconverters (P ‫؍‬ 0.046 by univariable analysis). In multivariable models, early setpoint viral loads in seroconverting partners were a complex function of (i) the viral load in the source partner, (ii) the gender of the seroconverter, (iii) specific HLA class I alleles in the newly infected partner, and (iv) sharing of HLA-I alleles between partners in a transmission pair. Each of these factors significantly and independently contributed to the set-point viral load in the newly infected partner, accounting for up to 37% of the variance observed and suggesting that many factors operate in concert to define the early virological phenotype in HIV-1 infection. The HIV-1 set-point viral load (VL) in infected individuals directly affects the transmission rate of the virus (1-3) and early disease progression (4-6). Recent studies have shown a trend of increasing set-point VLs over the last 30 years of the HIV-1 epidemic (7, 8), raising the possibility of both increasing transmission rates and virulence in treatment of naïve HIV-1 infection. A plausible explanation for this observation is viral adaptation to the host at the population level over time (9, 10), providing a further challenge for HIV-1 vaccine design. The determinants of set-point VL in newly infected individuals include viral genetic factors (11-13) and host genetic factors (14-16). Thus, to comprehensively define the role of underlying factors in determining early set-point VL, it is necessary to understand the complexity of the interaction between the transmitted founder virus, with its embedded footprints of the immune response of the transmitting source partner (TSP), and the de novo immune defense of the seroconverting partner (SC).We previously observed that cytotoxic T-lymphocyte (CTL) epitope escape mutations selected by immune pressure in the TSP can modulate the early set-point VL in the SC (11, 17), suggesting that mutations that would be expected to positively impact VL in the TSP can negatively impact VL in the seroconverter. This observation is consistent with our previous studies of the ZEHRP cohort and with other studies of heterosexual cohorts of limited size. These studies demonstrated a relatively weak correlation between VLs in TSPs and SCs in linked heterosexual transmission partners (18)(19)(20). In contrast, a more significant VL correlation was shown for a transmission pair cohort of men who have sex with men (MSM) in San Francisco (21), and a phylogenetic analysis of MSM in the Swi...