PD-1+ and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals

Abstract

The mechanisms responsible for the persistence of HIV-1 after many years of suppressive antiretroviral therapy (ART) have been only partially elucidated. Most of the studies investigating HIV-1 persistence have been performed with blood, although it is well known that germinal centers (GCs) within lymph nodes (LNs) serve as primary sites for HIV-1 replication. We sought to identify the memory CD4 T cell populations in blood and LNs that are responsible for the production of replication-competent and infectious HIV-1, as well as for active and persistent virus transcription in ART-treated (for 1.5-14.0 years), aviremic (<50 HIV RNA copies/ml) HIV-infected individuals. We demonstrate that LN CD4 T cells that express programmed cell death 1 (PDCD1; also known as PD-1), which are composed of about 65% T follicular helper cells as defined by the expression of the cell surface receptors CXCR5 and PD-1, are the major source of replication-competent HIV-1 and of infectious virus, as compared to any other (CXCR5(-)PD-1(-) and CXCR5(+)PD-1(-)) blood or LN memory CD4 T cell populations. LN PD-1(+) cells accounted for 46% and 96% of the total pools of memory CD4 T cells containing inducible replication-competent or infectious virus, respectively. Notably, higher levels of cell-associated HIV-1 RNA were present in LN PD-1(+) cells after long-term (up to 12 years) ART than in other memory CD4 T cell subpopulations. These results indicate that LN PD-1(+) cells are the major CD4 T cell compartment in the blood and LNs for the production of replication-competent and infectious HIV-1, and for active and persistent virus transcription in long-term-ART-treated aviremic individuals. Thus, these cells may represent a major obstacle to finding a functional cure for HIV-1 infection.

The human IL-15 superagonist ALT-803 directs SIV-specific CD8+ T cells into B-cell follicles

“…The IL-15 superagonist ALT-803 was generated by Altor BioScience as previously described. 6 All ALT-803 injections were given as IV bolus doses of either 6 mg/kg or 100 mg/kg. For BrdU injections, BrdU was suspended at 10 mg/mL in Hanks balanced salt solution (HyClone Laboratories, Logan, UT) and then injected IV in the saphenous vein at a rate of 2 to 3 mL/minute for a total dose of 60 mg/kg of BrdU.…”

“…In HIV elite controllers and antiretroviral therapy (ART)-treated patients, T FH cells are the major source of persistent HIV. 5,6 Accordingly, the development of therapeutic strategies that induce virus-specific CD8 1 T cells capable of infiltrating into the B-cell follicle to eliminate reactivated latently HIV-infected T FH is a major unmet goal of shock-and-kill approaches for achieving an immune-mediated HIV cure.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…Furthermore, Tfh cell populations in both LNs and blood constitute a major (although not the only) site of SIV/HIV latency in macaques/humans receiving antiretroviral therapy 171, 176, 177, 178, 179. GC Tfh cells are not only highly activated cells that are good targets for HIV‐1 infection but are also located in close proximity to FDCs, which are an important reservoir of infectious virus and can readily transmit infection to Tfh cells 180, 181, 182, 183.…”

Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells

“…+ T cells with a follicular Th cell polarization, known for their ability to support humoral immunity, harbor high levels of replication-competent HIV-1 in cART-treated individuals, most likely due to an anatomical location in immunologically privileged lymph node germinal centers (5). Less is known about the possible role that CD4 + T cells with alternative polarizations may play as viral reservoir sites.…”