Navigating the complexity of chronic HIV-1 associated immune dysregulation.

Despite successful viral suppression with antiretroviral therapy, chronic HIV-1 infection is associated with ongoing immune dysfunction. Investigation of the complex immune response in treated and untreated individuals with chronic HIV-1 infection is warranted. Immune alterations such as monocyte phenotype and Th-17/Treg ratios often persist years after the reduction in viraemia and predispose many individuals to long-term comorbidities such as cardiovascular disease or cancer. Furthermore, while there has been extensive research on the latent reservoir of treated patients with chronic HIV-1, which prevents the discontinuation of treatment, the mechanism behind this remains elusive and needs further investigation. In this review, we assist in navigating the recent research on these groups of individuals and provide a basis for further investigation.

CD73+ CD127high Long-Term Memory CD4 T Cells Are Highly Proliferative in Response to Recall Antigens and Are Early Targets in HIV-1 Infection.

HIV-1 infection rapidly leads to a loss of the proliferative response of memory CD4+ T lymphocytes, when cultured with recall antigens. We report here that CD73 expression defines a subset of resting memory CD4+ T cells in peripheral blood, which highly express the α-chain of the IL-7 receptor (CD127), but not CD38 or Ki-67, yet are highly proliferative in response to mitogen and recall antigens, and to IL-7, in vitro. These cells also preferentially express CCR5 and produce IL-2. We reasoned that CD73+ memory CD4+ T cells decrease very early in HIV-1 infection. Indeed, CD73+ memory CD4+ T cells comprised a median of 7.5% (interquartile range: 4.5-10.4%) of CD4+ T cells in peripheral blood from healthy adults, but were decreased in primary HIV-1 infection to a median of 3.7% (IQR: 2.6-6.4%; p = 0.002); and in chronic HIV-1 infection to 1.9% (IQR: 1.1-3%; p < 0.0001), and were not restored by antiretroviral therapy. Moreover, we found that a significant proportion of CD73+ memory CD4+ T cells were skewed to a gut-homing phenotype, expressing integrins α4 and ß7, CXCR3, CCR6, CD161 and CD26. Accordingly, 20% of CD4+ T cells present in gut biopsies were CD73+. In HIV+ subjects, purified CD73+ resting memory CD4+ T cells in PBMC were infected with HIV-1 DNA, determined by real-time PCR, to the same level as for purified CD73-negative CD4+ T cells, both in untreated and treated subjects. Therefore, the proliferative CD73+ subset of memory CD4+ T cells is disproportionately reduced in HIV-1 infection, but, unexpectedly, their IL-7 dependent long-term resting phenotype suggests that residual infected cells in this subset may contribute significantly to the very long-lived HIV proviral DNA reservoir in treated subjects.