Understanding the CD8 T-cell response in natural HIV control

Abstract

HIV-infected individuals who maintain control of virus without antiretroviral therapy (ART) are called HIV controllers. The immune responses of these individuals suppress HIV viral replication to low levels or, in the case of elite controllers, to undetectable levels. Although some research indicates a role for inferior virulence of the infecting viral strain in natural control, perhaps by way of defective Nef protein function, we find that the majority of research in HIV controllers highlights CD8 T cells as the main suppressor of viral replication. The most convincing evidence for this argument lies in the strong correlation between certain HLA-I alleles, especially B*57, and HIV control status, a finding that has been replicated by many groups. However, natural control can also occur in individuals lacking these specific HLA alleles, and our understanding of what constitutes an effective CD8 T-cell response remains an incomplete picture. Recent research has broadened our understanding of natural HIV control by illustrating the interactions between different immune cells, including innate immune effectors and antigen-presenting cells. For many years, the immune responses of the natural HIV controllers have been studied for clues on how to achieve functional cure in the rest of the HIV-infected population. The goal of a future functional cure to HIV is one where HIV-infected individuals’ immune responses are able to suppress virus long-term without requiring ART. This review highlights recent advances in our understanding of how HIV controllers’ natural immune responses are able to suppress virus.

Comprehensive analysis of HIV elite controllers’ and progressors’ transcriptional profiles from CD8+T lymphocytes demonstrates heterogeneity of pathways and master regulators, which may be essential for disease nonprogression

“…Little is known regarding the mechanisms governing viral control in ECs (11, 13, 18–22, 24), but it appears that cytotoxic and noncytotoxic responses of CD8 + lymphocytes play a major role. Naive CD8 + T lymphocytes recognize MHC-I restricted HIV antigens presented by dendritic cells in lymph nodes that cause their activation, proliferation, and differentiation into cytotoxic T lymphocytes.…”

“…Thus, CD8 + lymphocytes can also exhibit noncytotoxic anti-HIV functions through the secretion of chemokines that compete with HIV particles for the corresponding coreceptors (19). CD8 + lymphocytes from ECs have T-cell receptors capable of broader cross-recognition of mutated epitopes from HIV gag antigens, which may be a consequence of the presence of HLA-I polymorphisms, e.g., HLA-B*57 and B*27, that influence the selection of T cell clones in the thymus (18, 19, 22, 32). CD8 + lymphocytes from ECs do not demonstrate an “exhaustion” state and have preserved functions related to cytotoxic and noncytotoxic responses (18, 19, 22, 24), including the ability to degranulate and secrete cytokines with anti-HIV effects, such as MIP-1α/β, RANTES, IFN-γ, TNF-α, and IL-2.…”

“…Only cyclins D1 and D2 are expressed in all phases of the cell cycle; thus, the presence of their transcription in EC groups 2-4 and the absence of transcription of other cyclins may indicate normal CD8 + lymphocyte proliferation. CD8 + lymphocytes from ECs are known to preserve their ability to proliferate compared to progressors (22). The receptors of CD8 + cell growth factors were also upregulated in EC groups 2-4 but downregulated in untreated progressors (Table 3).…”

“…For instance, the androgen receptor gene is downregulated in EC groups 2 and 4, but its expression is not changed in progressors. It was shown that women are significantly overrepresented in the EC population compared to men (22). This finding can be explained by androgens’ influence on the immune system, including CD8 + lymphocytes (40).…”

Genetic and Environmental Interaction in Type 1 Diabetes: a Relationship Between Genetic Risk Alleles and Molecular Traits of Enterovirus Infection?

“…Whether different HLA class I allelic variants exhibit a different level of sensitivity to this mechanism remains to be established. Individuals carrying the T1D low-risk allele B*5701 have been reported to have very low risk for progression of HIV-infection to AIDS (so-called elite controllers) [71]. Whether certain HLA class I alleles could provide similar protection from infections caused by viruses associated with T1D remains to be investigated.…”