Both HLA-B*57 and Plasma HIV RNA Levels Contribute to the HIV-Specific CD8 ⁺ T Cell Response in HIV Controllers

Abstract

g 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 HIVspecific 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.

Long-Term Spontaneous Control of HIV-1 Is Related to Low Frequency of Infected Cells and Inefficient Viral Reactivation

“…Similar observations have been made in macaques spontaneously controlling simian immunodeficiency virus (SIV) SIVmac251 infection (10). In HICs, highly responsive CD8 ϩ T cells tend to have an effector phenotype (4,8,11), whereas weakly responsive CD8 ϩ T cells tend to have a resting memory phenotype (8,9). Weakly responsive CD8 ϩ T cells from HICs can regain their effector functions upon antigen stimulation (12), but their role in HIV-1 control in vivo is unclear.…”

“…We then examined whether the different amplitudes of HIV-specific CD8 ϩ T cell responses that we and others have observed in HICs (8,9,42) were related to the capacity of these patients' CD4…”

“…In particular, CD8 ϩ T cells from many HICs efficiently eliminate infected CD4 ϩ T cells ex vivo (4). Certain HLA class I alleles, such as B*57 and B*27, are overrepresented in HICs (4-7), but efficient anti-HIV CD8 ϩ T cell responses are not restricted to individuals carrying these alleles (8). In addition, potent HIV-specific CD8 ϩ T cell responses are not found in all HICs, at least during the chronic phase of infection (8,9).…”

“…Certain HLA class I alleles, such as B*57 and B*27, are overrepresented in HICs (4-7), but efficient anti-HIV CD8 ϩ T cell responses are not restricted to individuals carrying these alleles (8). In addition, potent HIV-specific CD8 ϩ T cell responses are not found in all HICs, at least during the chronic phase of infection (8,9). We have found that HIV-specific CD8 ϩ T cell responses in some HICs enrolled in the ANRS CO21 cohort wane over time, yet the plasma viral load remains undetectable (unpublished observations).…”

Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8+T-Cell Responses

“…Differences in T-cell responses between SR and WR cannot be explained by their expression of HLA class I alleles because they are overrepresented to the same extent in both groups (17). This raises the question of the real contribution of CD8 ϩ T-cell responses to the maintenance of long-term viral control in these patients.…”