Replicative Capacity of Human Immunodeficiency Virus Type 1 Transmitted from Mother to Child Is Associated with Pediatric Disease Progression Rate

Self Cite

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: 82%

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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“…However, more detailed studies on the determinants of HIV-1 containment in the presence of "protective" HLA class I alleles, such as HLA-B*57 and HLA-B*27, have pointed out that mutations are reproducibly selected in the immunodominant epitopes (2), even when viral replication is still under control (31,32). In fact, it seems that viral containment is even linked to these escape mutations by their strong impact on replication capacity (14,36). Importantly, reduced fitness associated with some escape mutations can be restored when secondary mutations outside the epitope region are selected (43).…”

Section: Discussionmentioning

confidence: 99%

Escape from a Dominant HLA-B*15-Restricted CD8 ⁺ T Cell Response against Hepatitis C Virus Requires Compensatory Mutations outside the Epitope

Ruhl

Chhatwal

Strathmann

et al. 2012

Antiviral CD8 ؉ T cells are a key component of the adaptive immune system against hepatitis C virus (HCV).For the development of immune therapies, it is essential to understand how CD8 ؉ T cells contribute to clearance of infection and why they fail so often. A mechanism for secondary failure is mutational escape of the virus. However, some substitutions in viral epitopes are associated with fitness costs and often require compensatory mutations. We hypothesized that compensatory mutations may point toward epitopes under particularly strong selection pressure that may be beneficial for vaccine design because of a higher genetic barrier to escape. We previously identified two HLA-B*15-restricted CD8 ؉ epitopes in NS5B (LLRHHNMVY 2450-2458 and SQRQKKVTF 2466-2474 ), based on sequence analysis of a large HCV genotype 1b outbreak. Both epitopes are targeted in about 70% of HLA-B*15-positive individuals exposed to HCV. Reproducible selection of escape mutations was confirmed in an independent multicenter cohort in the present study. Interestingly, mutations were also selected in the epitope flanking region, suggesting that compensatory evolution may play a role. Covariation analysis of sequences from the database confirmed a significant association between escape mutations inside one of the epitopes (H2454R and M2456L) and substitutions in the epitope flanking region (S2439T and K2440Q). Functional analysis with the subgenomic replicon Con1 confirmed that the primary escape mutations impaired viral replication, while fitness was restored by the additional substitutions in the epitope flanking region. We concluded that selection of escape mutations inside an HLA-B*15 epitope requires secondary substitutions in the epitope flanking region that compensate for fitness costs.A ntiviral CD8 ϩ T cells are one of the key components of the adaptive immune system against hepatitis C virus (HCV). During acute infection, HCV-specific CD8 ϩ T cells are activated in the majority of patients (24, 38). Nevertheless, viral persistence is observed in 50 to 80% of patients. These patients with chronic HCV infection are at risk of progressive liver disease and liver cancer. For the development of immune therapies against HCV, it is essential to understand how CD8 ϩ T cells contribute to clearance of infection and why they fail so often. Different mechanisms for CD8 ϩ T cell failure have been described. The proposed mechanisms include primary failure by lack or impairment of priming of specific CD8 ϩ T cells upon HCV infection, as well as secondary failure after the initial priming (reviewed in reference 40). Studies of patients with acute HCV infection suggest that CD8 ϩ T cells are activated in most patients, irrespective of the outcome of infection (6), which supports an important role for secondary failure of HCV-specific CD8 ϩ T cells.Upon transition from acute to chronic HCV infection, the frequency of specific CD8 ϩ T cells declines (6). Moreover, CD8 ϩ T cells from patients with chronic HCV infection produce fewer cytokines and p...

“…Second, individuals with acute infection are highly contagious (93)-in a study of HIV-1-discordant couples from Uganda, 43.5% of incident cases of heterosexual HIV-1 transmission involved donor/source partners with acute infection (68). Third, acute infection sets the stage for other pathophysiological events, including immune dominance (3,25), viral genetic drift or recombination (20,94), and immune escape (39,64,69,76,89). It is conceivable that relatively effective control of the initial "viral burst," as seen frequently in SCs with B*44 and B*57 during acute infection, can limit viral reservoirs and alter other pathways of HIV-1 pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

Human Leukocyte Antigen Variants B44 and B57 Are Consistently Favorable during Two Distinct Phases of Primary HIV-1 Infection in Sub-Saharan Africans with Several Viral Subtypes

Tang

Cormier

Gilmour

et al. 2011

As part of an ongoing study of early human immunodeficiency virus type 1 (HIV-1) infection in sub-Saharan African countries, we have identified 134 seroconverters (SCs) with distinct acute-phase (peak) and early chronic-phase (set-point) viremias. SCs with class I human leukocyte antigen (HLA) variants B*44 and B*57 had much lower peak viral loads (VLs) than SCs without these variants (adjusted linear regression beta values of ؊1.08 ؎ 0.26 log 10 [mean ؎ standard error] and ؊0.83 ؎ 0.27 log 10 , respectively; P < 0.005 for both), after accounting for several nongenetic factors, including gender, age at estimated date of infection, duration of infection, and country of origin. These findings were confirmed by alternative models in which major viral subtypes (A1, C, and others) in the same SCs replaced country of origin as a covariate (P < 0.03). Both B*44 and B*57 were also highly favorable (P < 0.03) in analyses of set-point VLs. Moreover, B*44 was associated with relatively high CD4 ؉ T-cell counts during early chronic infection (P ‫؍‬ 0.02). Thus, at least two common HLA-B variants showed strong influences on acute-phase as well as early chronic-phase VL, regardless of the infecting viral subtype. If confirmed, the identification of B*44 as another favorable marker in primary HIV-1 infection should help dissect mechanisms of early immune protection against HIV-1 infection.HIV-1 viral load (VL or viremia), in the typical form of viral RNA concentration in plasma, has both epidemiological and clinical implications because of its dual impact on transmission (18,30,71) and on the rate of disease progression (58, 59). In most studies, a quantitative measure of VL is used without reference to estimated date of infection (EDI), under the assumption that patients are seldom observed during acute-phase (peak) infection and that the early chronic-phase (set-point) VL is usually stable for years in patients with no apparent manifestations of immunodeficiency. Factors known or suspected to influence VL range from viral mutations (changes in replication fitness or switches in coreceptor tropism) (15,28,39,72) to host genes that govern innate and adaptive immune responses (54,75,81,83,84,86).Within the human nuclear genome, human leukocyte antigen (HLA) class I genes are the most convincing (and universally applicable) quantitative trait loci for HIV-1 viremia (14,16,17,66). However, the individual HLA alleles, haplotypes, and supertypes with reported impacts on HIV-1 VL are not always clear because their distribution and patterns of linkage disequilibrium often differ from one population to another (7,53,63). Consensus findings have been limited to a few variants like B*27 and B*57 (9, 80), although more recent work based on African cohorts has yielded consensus results for additional variants, including A*74, B*13, and B*81, that are often favorable (49, 81). The HLA class I heavy chains encoded by these alleles differentially present highly conserved viral epitopes for cytotoxic T-lymphocyte (CTL) responses (5,29,39). Su...