HIV-1 is able to create lasting reservoirs of virally infected cells that persist life-long and are extremely difficult to eradicate, thus necessitating indefinite antiretroviral therapy. Large numbers of studies suggest that CD4+ T cells represent the major, and possibly the only cell type supporting HIV-1 long-term persistence. However, the ability to serve as long-term viral reservoirs may be confined to certain subpopulations of CD4+ T cells with specific functional and developmental characteristics that HIV-1 can selectively exploit to propagate long-term viral survival within the host. Identification of CD4+ T-cell subtypes that serve as hotspots for viral persistence may be critical for designing strategies to purge the immune system of persisting viral reservoirs.
Developmentally immature, long-lasting CD4+ memory T-cell populations seem to contain the majority of latently HIV-1-infected cells that persist despite antiretroviral therapy in the peripheral blood. Emerging data suggest that functional polarization toward a T helper 17 (Th17), a T follicular helper cell or a regulatory T-cell lineage may also be associated with an increased ability to serve as a viral reservoir site. Atypical T cells such a γδ CD4+ T cells or tissue-resident memory CD4+ T cells may be predestined to serve as sites for HIV-1 persistence in specific tissues, but will require additional exploration in future studies.
Recent advances have increased awareness for the profound diversity and complexity of CD4+ T-cell subpopulations serving as sites for HIV-1 persistence. Continuous technological and methodological improvements to interrogate viral reservoirs in distinct CD4+ T-cell subpopulations may allow to define a more complete landscape of the HIV-1 reservoir composition in different T-cell subpopulations.
aInfectious Disease Division, Brigham and Women's Hospital and Massachusetts General Hospital
bRagon Institute of MGH, MIT and Harvard, Cambridge
cHarvard Medical School, Boston, Massachusetts, USA
Correspondence to Mathias Lichterfeld, MD, PhD, Infectious Disease Division, Brigham and Women's Hospital, 65 Landsdowne Street, Cambridge, MA 02139, USA. E-mail: firstname.lastname@example.org