Emergence of Individual HIV-Specific CD8 T Cell Responses during Primary HIV-1 Infection Can Determine Long-Term Disease Outcome

Abstract

Events during primary HIV- 0009). While neither the breadth nor the magnitude of HIV-specific CD8 T cell responses showed an influence on the early viral set point, a broader HIV-specific CD8 T cell response targeting epitopes within HIV-1 Gag duringprimary HIV-1 infection was associated with slower disease progression. Moreover, the induction of certain HIV-specific CD8 T cell responses-but not others-significantly influenced the time to ART initiation. Individual epitope-specific CD8 T cell responses contribute significantly to HIV-1 disease control, demonstrating that the specificity of the initial HIV-specific CD8 T cell response rather than the restricting HLA class I molecule alone is a critical determinant of antiviral function. IMPORTANCEUnderstanding which factors are involved in the control of HIV-1 infection is critical for the design of therapeutic strategies for patients living with HIV/AIDS. Here, using a cohort of over 600 individuals with acute and early HIV-1 infection, we assessed in unprecedented detail the individual contribution of epitope-specific CD8 T cell responses directed against HIV-1 to control of viremia and their impact on the overall course of disease progression.

Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

“…As responses to many additional potential HIV epitopes could not be tested due to lack of additional epitopes for the class I tetramers used, and lack of any tetramers for four of the subject’s class I alleles, these data likely underestimated the magnitude of HIV-specific responses. The use of tetramers also enabled us to determine that acute infection was associated with impaired IFN-γ production, but this increased following the return of CD8 + T cell activation to baseline, consistent with earlier studies (Radebe et al, 2011; Streeck et al, 2014; Trautmann et al, 2012). It is conceivable that the aforementioned limitations of IFN-γ as readout contributed to the lack of association between breadth or magnitude and viral load set point reported in recent acute infection studies (Radebe et al, 2011; Streeck et al, 2014).…”

“…The use of tetramers also enabled us to determine that acute infection was associated with impaired IFN-γ production, but this increased following the return of CD8 + T cell activation to baseline, consistent with earlier studies (Radebe et al, 2011; Streeck et al, 2014; Trautmann et al, 2012). It is conceivable that the aforementioned limitations of IFN-γ as readout contributed to the lack of association between breadth or magnitude and viral load set point reported in recent acute infection studies (Radebe et al, 2011; Streeck et al, 2014). Our data show that the use of autologous infected cells as targets and the use of tetramers allowed for a more sensitive estimation of virus-specific CD8 + T cell responses during the early phase of the infection.…”

Very early antiretroviral therapy permits CD8 T cells to keep HIV reservoirs at bay

“…We first learned that after undergoing rapid expansion following acute HIV infection, CD8 T cells waned and became hypo-functional or "exhausted" after a few months of infection (7). The quality of CD8 T cell response contributes to the establishment of a viral set point in each patient that in turn has been shown to predict the time of the development of AIDS events and CD4 T cell decay (8,9). Furthermore, the contribution of CD8 T cell function was illustrated by the ability of a fraction of elite controllers carrying distinctive HLA-B57 or HLA-B27 alleles to suppress viral replication (10); and by viral escape due to the immune pressure observed after early infection.…”

Clinical Control of HIV-1 by Cytotoxic T Cells Specific for Multiple Conserved Epitopes

“…A significance threshold for q of Ͻ0.2 was employed. A recent study investigated CD8 ϩ T cell responses to 286 defined epitopes in 620 mainly Caucasian individuals with primary HIV-1 infection and showed that the specificity of the initial HIVspecific CD8 T cell response is a critical determinant of antiviral function rather than the restricting HLA class I molecule alone (38). In contrast, we here demonstrated that the breadths and the total magnitude of the T cell responses restricted by HLA-B*52:01 or HLA-B*67:01 were negatively correlated with pVL, suggesting that the multiple CTLs restricted by 2 protective alleles synergistically controlled HIV-1 in the Japanese individuals.…”