[Show abstract][Hide abstract] ABSTRACT: Some HIV controllers (HICs) experience CD4+T cell count loss and/or lose their ability to control HIV. In this study, we investigated the rate of immunologic and/or virologic progression (ImmP/VirP) and its determinants in the ANRS CO21/CODEX cohort. Immunologic progression was defined as a lasting fall in CD4+T cell count below 350/mm3 or more than 200/mm3 with a baseline count below 600/mm3. Virologic progression was defined as a HIV viral load (VL) above 2000 copies/mL on two consecutive determinations. Clinical characteristics, immune activation, ultrasensitive HIV VL and total HIV DNA were analyzed. Disease progression was observed in 15 of the 217 patients followed up between 2009 and 2013 (ImmP, n = 10; VirP, n = 5). Progressors had higher ultrasensitive HIV RNA levels at inclusion (i.e. 1-2 years before progression) than non-progressors. ImmP had also lower CD4+T cell nadir and CD4+T cell count at inclusion, and VirP had higher HIV DNA levels in blood. T cell activation and IP10 levels at inclusion were significantly higher in ImmP than in non-progressors. In summary, the lasting loss of CD4+T cells, residual HIV replication and basal levels of immune activation appear to be major determinants of progression in HICs. These factors should be considered for adjusting their follow-up.
[Show abstract][Hide abstract] ABSTRACT: During HIV infection, increase in CD57 expression among CD8+ T cells has been associated to immune senescence and defective immune responses. Interestingly, CD57 expressing CD8+ T cells exhibit dual profile being simultaneously highly cytotoxic (terminally differentiated effectors) and poorly proliferative (replicative senescent). Recent publications point towards a positive role of CD57 expressing CD8+ T cell subsets, presumably due to their high cytolytic activity. We further investigated the phenotype of CD57 expressing CD8+ T cells in healthy donors and during HIV infection combining CD57 expression to Eomesodermin (EOMES), a T-box transcription factor which determine, coordinately with T-bet, effector and memory CD8+ T cell differentiation. We defined in healthy donors two functionally distinct CD57 expressing CD8+ T cell subsets exhibiting different levels of EOMES expression: EOMES(hi)CD57+ and EOMES(int)CD57+ CD8+ T cells. EOMES(hi)CD57+ cells exhibited low cytotoxic activity but preserved proliferative capacity and IL-7 receptor expression, whereas EOMES(int)CD57+ exhibited obvious cytotoxic functions and more terminal differentiated phenotype. We next performed a similar analysis in different contexts of HIV infection: primary infected patients, long-term viremic patients, aviremic patients treated with antiretroviral therapy and HIV controllers, demonstrating higher percentage of CD57 expressing cells in all HIV infected patients regardless of virological status. When heterogeneity in EOMES expression among CD57 cells was taken into account, we detected significantly higher proportions of EOMES(hi)CD57+ cells among HIV-specific and non-specific CD8+ T cells from HIV-controllers compared to aviremic antiretroviral-treated patients and viremic patients. Importantly, such peculiar non-terminally differentiated EOMES(hi)CD57+ phenotypic profile was associated with viral control.
Full-text · Article · Aug 2014 · Journal of Virology
[Show abstract][Hide abstract] ABSTRACT: Background
HIV controllers (HIC) are rare HIV-1-infected patients who exhibit spontaneous viral control. HIC have high frequency of CD38−/HLA-DR+ HIV-specific CD8+ T cells. Here we examined the role of this subset in HIC status.
Materials and Methods
We compared CD38−/HLA-DR+ CD8+ T cells with the classical CD38+/HLA-DR+ activated phenotype in terms of 1) their activation status, reflected by CD69, CD25, CD71, CD40 and Ki67 expression, 2) functional parameters: Bcl-2 expression, proliferative capacity, and IFN-γ and IL-2 production, and 3) cytotoxic activity. We also investigated how this particular profile is generated.
Compared to CD38+/HLA-DR+ cells, CD38−/HLA-DR+ cells exhibited lower expression of several activation markers, better survival capacity (Bcl-2 MFI, 367 [134–462] vs 638 [307–747], P = 0.001), higher frequency of polyfunctional cells (15% [7%–33%] vs 21% [16%–43%], P = 0.0003), greater proliferative capacity (0-fold [0–2] vs 3-fold –, P = 0.007), and higher cytotoxicity in vitro (7% [3%–11%] vs 13% [6%–22%], P = 0.02). The CD38−/HLA-DR+ profile was preferentially generated in response to low viral antigen concentrations.
These data highlight the role of CD38−/HLA-DR+ HIV-specific CD8+ T cell cytotoxicity in HIC status and provide insights into the mechanism by which they are generated. Induction of this protective CD8+ subset may be important for vaccine strategies.
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND:: Although HIV controllers (HICs) achieve long-term control of viremia in the absence of antiretroviral therapy (ART), they display marked immune activation. The levels of inflammatory biomarkers in HICs and the biomarkers' relationships with immunologic and virologic status have yet to be fully characterized.
DESIGN:: A cohort study.
METHODS:: Plasma levels of seven biomarkers [tumor necrosis factor (TNF)α, interleukin (IL)6, IL10, IP10, MCP1, sCD14, sCD163] were compared in 70 HICs, 33 HIV-1-infected, treatment-naive noncontrollers (viremic patients), 30 ART-treated patients and 40 healthy donors. In HICs, we investigated the interplay between biomarkers, cell activation and the CD4 T-cell count.
RESULTS:: HICs had higher levels of IP10, TNFα and sCD14 than healthy donors did (P < 0.01 for each). Also, TNFα and sCD14 levels of the HICs were similar to those measured in viremic and ART-treated patients. However, the levels of IL6 and IL10 were significantly lower in HICs than in viremic or ART-treated patients. In HICs, only IP10 levels differed significantly from those in both healthy donors and viremic patients, and were positively correlated with the expression of CD8 and CD4 T-cell activation markers. The IP10 levels of HICs were still elevated 12 and 24 months after the initial assay. Lastly, IP10 levels at enrollment were negatively correlated with the CD4 T-cell count at enrollment and 12 months later.
CONCLUSION:: HICs display a number of inflammatory features associated with persistent T-cell immune activation.
[Show abstract][Hide abstract] ABSTRACT: CD8+ T cell responses are thought to play an important role during HIV infection, particularly in HIV controllers (HIC) in whom
viral replication is spontaneously controlled without any treatment. We have demonstrated that CD8+ T cells from these subjects are able to suppress viral replication in vitro. In parallel, HIV-specific CD8+ responses were shown to be strong and of high quality, with proliferative abilities and cytotoxic capacities, in HIC. The
HLA-B*57 allele, which is associated with a better clinical outcome in HIV infection, is overrepresented in HIC. However,
we showed that these patients constitute a heterogeneous group that includes subjects who present weak suppression of viral
replication in vitro and HIV-specific responses. We performed an extensive study of 101 HIC (49 HLA-B*57+ and 52 HLA-B*57−) to determine the impact of HLA-B*57 on the HIV-specific CD8+ response. The HLA-B*57-restricted response displayed better qualitative features, such as higher functional avidity, higher
proliferation capacity, and a higher level of cytokine production, than responses not restricted by HLA-B*57. However, the
highest frequencies of HIV-specific CD8+ T cells were observed only in a subset of HLA-B*57+ subjects. They were tightly associated with the ability to suppress viral replication in vitro. In contrast, the subset of HLA-B*57+ subjects with a weak ability to suppress viral replication had significantly lower ultrasensitive viral loads than all the
other groups of controllers. In conclusion, both HLA-B*57 and the amount of ultrasensitive viral load seem to play a role
in HIV-specific CD8+ T cell responses in HIC.
Full-text · Article · Oct 2013 · Journal of Virology
[Show abstract][Hide abstract] ABSTRACT: The role of Antibody-dependent cellular cytotoxicity (ADCC) responses in HIV-1 controllers is still unclear due to the heterogeneity of these patients. We analyzed 67 HIV-1 controllers and found significantly higher levels of ADCC antibodies in controllers versus viremic subjects (p = 0.017). Moreover, multivariate analysis revealed significantly higher ADCC titers in HLA B57- controllers compared to HLA-B57+ ones (p = 0.0086). These data suggest a role for ADCC in immune control of HIV, especially in HLA B57 negative controllers.
[Show abstract][Hide abstract] ABSTRACT: HIV-controllers spontaneously maintain HIV viraemia at an undetectable level. We aimed to describe the delay to control from seroconversion, the duration of control, and risk factors for losing control.
HIV-controllers were identified from a pooled dataset of 24 seroconverter cohorts from Europe, Australia and Canada (CASCADE). HIV-controllers had ≥5 consecutive viral loads (VL) <400/500 copies/mL, while ART-naïve, for ≥5 years after seroconversion. End of control was defined as two consecutive VL >2000 copies/mL.Duration of control was described using Kaplan-Meier estimates; factors associated with duration of control identified using a Cox model. CD4 count evolution during control was described using a mixed model.
Of 9,896 eligible seroconverters, we identified 140 (1.4%) HIV-controllers, the largest database of HIV-controllers followed from seroconversion. For 64 with VL measured within 24 months from seroconversion, median delay to control was 16.7 (IQR: 7.8-37.9) months. Probability of maintaining control 20 years after seroconversion was 0.74 (95% confidence interval (CI): 0.64-0.85). Occurrence of blips followed by return to undetectability did not increase the risk of loss of control (hazard ratio: 0.81 (95% CI: 0.10-6.70). However, CD4 cell loss during control was significantly accelerated in individuals with blips.
In most individuals, control occurred rapidly after seroconversion; however, >3 years were required to achieve control in 25% of HIV-controllers. Control may be sustained even while CD4 levels are below 500 cells/mm, opening important new perspectives to understand the physiopathology underlying control.
No preview · Article · Aug 2013 · AIDS (London, England)
[Show abstract][Hide abstract] ABSTRACT: The expression of certain HLA class I alleles, including HLA-B*27 and HLA-B*57, is associated with better control of HIV-1 infection, but the mechanisms responsible are not fully understood. We sought evidence that pressure from the human restriction factor TRIM5α (hTRIM5α) could contribute to viral control. The hTRIM5α sensitivity of viruses from both HLA-B*57+ and HLA-B*27+ patients who spontaneously controlled viral replication, but not viruses from viremic patients expressing these alleles, was significantly greater than that of viruses from patients not expressing these protective HLA-B alleles. Overall, a significant negative correlation between hTRIM5α sensitivity and viral load was observed. In HLA-B*57+ patients, the T242N mutation in the HLA-B*57-restricted TW10 CTL epitope was strongly associated with hTRIM5α sensitivity. In HLA-B*27+ controllers, hTRIM5α sensitivity was associated with a significant reduction in emergence of key CTL mutations. In several patients, viral evolution to avoid hTRIM5α sensitivity was observed, but could be associated with reduced viral replicative capacity. Thus, in individuals expressing protective HLA-B alleles, the combined pressures exerted by CTL, hTRIM5α and capsid structural constraints can prevent viral escape both by impeding the selection of necessary resistance/compensatory mutations, and forcing the selection of escape mutations that increase hTRIM5α sensitivity or impair viral replicative capacity.
Full-text · Article · Jul 2013 · Journal of Virology
[Show abstract][Hide abstract] ABSTRACT: The strong CD8+ T-cell-mediated HIV-1-suppressive capacity found in a minority of HIV-infected patients in chronic infection is associated with spontaneous control of viremia. However, it is still unclear whether such capacities were also present earlier in the CD8+ T cells from non controller patients and then lost as a consequence of uncontrolled viral replication. We studied 50 patients with primary HIV-1-infection to determine whether strong CD8+ T-cell-mediated HIV suppression is more often observed at that time. Despite high frequencies of polyfunctional HIV-specific CD8+ T-cells and a strong CD4+ T-helper response, CD8+ T-cells from 48 patients lacked strong HIV-suppressive capacities ex vivo. This indicates that the superior HIV-suppressive capacity of CD8+ T-cells from HIV controllers is not a general characteristic of the HIV-specific CD8+ T cell response in primary HIV infection.
[Show abstract][Hide abstract] ABSTRACT: The capacity of the immune system to adapt to rapidly evolving viruses is a primary feature of effective immunity, yet its molecular basis is unclear. Here, we investigated protective HIV-1-specific CD8(+) T cell responses directed against the immunodominant p24 Gag-derived epitope KK10 (KRWIILGLNK263-272) presented by human leukocyte antigen (HLA)-B(∗)2705. We found that cross-reactive CD8(+) T cell clonotypes were mobilized to counter the rapid emergence of HIV-1 variants that can directly affect T cell receptor (TCR) recognition. These newly recruited clonotypes expressed TCRs that engaged wild-type and mutant KK10 antigens with similar affinities and almost identical docking modes, thereby accounting for their antiviral efficacy in HLA-B(∗)2705(+) individuals. A protective CD8(+) T cell repertoire therefore encompasses the capacity to control TCR-accessible mutations, ultimately driving the development of more complex viral escape variants that disrupt antigen presentation.
[Show abstract][Hide abstract] ABSTRACT: Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.
[Show abstract][Hide abstract] ABSTRACT: T cell activation levels, viral load and CD4(+) T cell counts at early stages of HIV-1 infection are predictive of the rate of progression towards AIDS. We evaluated whether the inflammatory profile during primary HIV-1 infection is predictive of the virological and immunological set-points and of disease progression. We quantified 28 plasma proteins during acute and post-acute HIV-1 infection in individuals with known disease progression profiles. Forty-six untreated patients, enrolled during primary HIV-1 infection, were categorized into rapid progressors, progressors and slow progressors according to their spontaneous progression profile over 42 months of follow-up. Already during primary infection, rapid progressors showed a higher number of increased plasma proteins than progressors or slow progressors. The plasma levels of TGF-β1 and IL-18 in primary HIV-1 infection were both positively associated with T cell activation level at set-point (6 months after acute infection) and together able to predict 74% of the T cell activation variation at set-point. Plasma IP-10 was positively and negatively associated with, respectively, T cell activation and CD4(+) T cell counts at set-point and capable to predict 30% of the CD4(+) T cell count variation at set-point. Moreover, plasma IP-10 levels during primary infection were predictive of rapid progression. In primary infection, IP-10 was an even better predictor of rapid disease progression than viremia or CD4(+) T cell levels at this time point. The superior predictive capacity of IP-10 was confirmed in an independent group of 88 HIV-1 infected individuals. Altogether, this study shows that the inflammatory profile in primary HIV-1 infection is associated with T cell activation levels and CD4(+) T cell counts at set-point. Plasma IP-10 levels were of strong predictive value for rapid disease progression. The data suggest IP-10 being an earlier marker of disease progression than CD4(+) T cell counts or viremia levels.
[Show abstract][Hide abstract] ABSTRACT: NKG2D mediates an important co-stimulatory pathway in CD8 T cells. In HIV infection, we found that NKG2D expression on both total and HIV-specific CD8 T cells was significantly lower in viremic patients than in HIV controllers. Antiretroviral therapy partially restored NKG2D expression on HIV-specific CD8 T cells. We observed a negative correlation between the respective expression levels of CD38 and NKG2D on total CD8 and HIV-specific CD8 T cells. The maintenance of NKG2D expression on CD8 T cells in HIV controllers may contribute to better cell function.