The Dual Impact of HIV-1 Infection and Aging on Naïve CD4+ T-Cells: Additive and Distinct Patterns of Impairment

Abstract

HIV-1-infected adults over the age of 50 years progress to AIDS more rapidly than adults in their twenties or thirties. In addition, HIV-1-infected individuals receiving antiretroviral therapy (ART) present with clinical diseases, such as various cancers and liver disease, more commonly seen in older uninfected adults. These observations suggest that HIV-1 infection in older persons can have detrimental immunological effects that are not completely reversed by ART. As naïve T-cells are critically important in responses to neoantigens, we first analyzed two subsets (CD45RA+CD31+ and CD45RA+CD31-) within the naïve CD4+ T-cell compartment in young (20–32 years old) and older (39–58 years old), ART-naïve, HIV-1 seropositive individuals within 1–3 years of infection and in age-matched seronegative controls. HIV-1 infection in the young cohort was associated with lower absolute numbers of, and shorter telomere lengths within, both CD45RA+CD31+CD4+ and CD45RA+CD31-CD4+ T-cell subsets in comparison to age-matched seronegative controls, changes that resembled seronegative individuals who were decades older. Longitudinal analysis provided evidence of thymic emigration and reconstitution of CD45RA+CD31+CD4+ T-cells two years post-ART, but minimal reconstitution of the CD45RA+CD31-CD4+ subset, which could impair de novo immune responses. For both ART-naïve and ART-treated HIV-1-infected adults, a renewable pool of thymic emigrants is necessary to maintain CD4+ T-cell homeostasis. Overall, these results offer a partial explanation both for the faster disease progression of older adults and the observation that viral responders to ART present with clinical diseases associated with older adults.

Critical role of CD4 T cells in maintaining lymphoid tissue structure for immune cell homeostasis and reconstitution

“…20,38,58,[61][62][63] This depletion strongly correlates with the depletion of memory CD4 T-cell population and disease progression 58,64,65 before initiation of HAART. Furthermore, the continuous deficiency of naive T cells also correlates with increasing incidence of non-AIDS-related clinical events, such as cardiovascular disease, liver disease, and non-AIDSrelated cancer, [26][27][28][29]64 and increased susceptibility to bacterial infections. 30 These observations suggest that naive T cells play a critical role in the pathogenesis of HIV infection.…”

Causes and outcome of hospitalization among HIV-infected adults receiving antiretroviral therapy in Mulago hospital, Uganda

“…HIV and aging are thought to cause additive depletion of naïve T-cells as well as replicating senescence of T-lymphocytes, which effects cause poor treatment outcomes in patients with advanced age when compared to younger patients 42 . Initiating ART at higher CD4+ counts in older patients could improve outcomes.…”

Pathogenicity and Mucosal Transmissibility of the R5-Tropic Simian/Human Immunodeficiency Virus SHIV AD8 in Rhesus Macaques: Implications for Use in Vaccine Studies

“…Because CCR5 is not expressed on naïve CD4 ϩ T lymphocytes, one could ask why this T cell subset is lost during SHIV AD8 infections of macaques. It is now recognized that deple- tion of this T lymphocyte subset is a prominent feature of chronic HIV-1 infections in the absence of coreceptor switching (23,42) and has been reported to occur in SIVsm543-infected rhesus macaques (25,32), but not in SIVmac239-infected monkeys (39). Loss of naive CD4 ϩ T cells is also characteristic of R5 SHIV AD8…”