HIV Replication and Persistence in T Follicular Helper Cells

Following up on the recent post on T follicular helper cells (TFH), a study published on December 17th in the Journal of Experimental Medicine reports that TFH represent a major site of HIV replication and persistence. The finding is not necessariy surprising, because lymph node studies conducted in the late 1980s and early 1990s showed that CD4 T cells in areas named germinal centers bore a great burden of HIV infection, and it is now known that this is where TFH locate during an immune response. But it was not previously understood that these CD4 T cells comprise a discrete subset, and TFH are now becoming increasingly well characterized in terms of both identifying features (such as surface markers and cytokine secretion) and their function in providing help to B cells.

Matthieu Perreau and colleagues from the University of Lausanne investigated TFH in three different groups of HIV-positive individuals:

• 23 with untreated chronic infection and viral load >5,000 copies/mL

• 14 on antiretroviral therapy (ART) with viral load below 20 copies/mL

• 3 long-term non-progressors (LTNP) with low viral load (less than 1,000 copies/mL)

A control group of 13 HIV-negative individuals was also included. The study confirmed the prior finding that TFH are significantly expanded in the lymph nodes of people with HIV compared to controls and that this expansion correlates with alterations in B cell subsets (a decline in long-lived resting naïve and memory B cells and an increase in short-lived activated B cells). The percentage of TFH correlated significantly with peripheral blood HIV viral load (r=0.6035, p=0.002). Suppression of HIV replication by ART reduced TFH levels and shifted B cell subsets back toward the distribution observed in controls. Echoing and extending the previous research by Madelene Lindqvist, a substantial proportion of the TFH were found to be specific for HIV, with responses to Gag and Pol proteins more commonly detected than those against Env (based on a test evaluating cytokine production after stimulation with Gag, Pol or Env peptides).

An analysis of the different CD4 T cell populations present in lymph nodes revealed that TFH contained the greatest amount of HIV DNA: assuming 1 HIV DNA copy per cell, approximately 5% of the TFH population was infected. After 72 weeks of ART there was a 1.5-2 log drop in the number of TFH containing HIV DNA, but a reservoir of infected cells remained detectable. Cell culture experiments showed that TFH were highly susceptible to HIV infection and replication compared to other CD4 T cell subsets, with the difference being most notable among the LTNP. The expression of the proliferation marker Ki67 by TFH was found to correlate with HIV DNA levels and ability to support HIV replication in vitro. Consistent with the elevation in immune activation that occurs in HIV, the proportion of TFH expressing Ki67 was 50% higher in the untreated HIV-positive individuals compared to HIV-negative controls.

The discussion section of the paper highlights several implications of the results, including:

• HIV itself -- as opposed to other potential factors, like microbial translocation -- appears to be the main driving force behind TFH activation and expansion, and the associated dysregulation of B cells.

• The preferential infection of TFH likely contributes to viral persistence, because germinal centers have been shown to offer limited access to CD8 T cells (which might otherwise kill HIV-infected cells). Follicular dendritic cells in lymph nodes have also long been known to be sites of extensive trapping of HIV virions, providing an ongoing source of viruses to infect TFH.

• The involvement of TFH in responses to new pathogens and vaccines offers an explanation for the reported association between intercurrent infections and vaccinations and transient HIV viral load increases (activation of TFH by these stimuli provides additional targets for HIV replication).

• The expression of certain cell surface markers (such as PD-1) by TFH may offer a means of targeting this population with interventions designed to reduce HIV persistence. A human trial of an antibody targeting PD-1 is currently in the works at the AIDS Clinical Trials Group (for more background see this recent short review "Novel Approaches to Curing HIV" by the principal investigator for the trial, Hiroyu Hatano).

Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.