Research has documented that HIV infection is associated with significantly increased scarring damage to lymphoid tissue, termed fibrosis. Fibrosis can be quantified by measuring the deposition of collagen, and the amount of lymphoid tissue fibrosis in HIV-positive people has been shown to correlate directly with CD4 T cell depletion. A paper published toward the end of last year by Timothy Schacker’s group at the University of Minnesota describes results of an analysis of gut-associated lymphoid tissue (GALT) fibrosis in untreated HIV controllers and HIV-positive people on ART, compared to HIV-negative controls and the one person considered cured of HIV, Timothy Brown. The study was previously presented in part at CROI 2013.
On average, the amount of GALT fibrosis was significantly greater in all HIV-positive groups compared to HIV-negative controls. No significant differences were observed between the various groups of HIV-positive participants. Timothy Brown showed levels of fibrosis comparable to the study participants without HIV infection. The results indicate that, in most cases, HIV suppression—whether by ART or in untreated elite controllers—is insufficient to reverse or avert fibrosis. Although only very tentative conclusions can be drawn from a single individual, it appears that curing HIV infection has been more successful in reversing the problem in Timothy Brown. One caveat is that, although the difference is significant on average, there are some individuals in each of the HIV-positive groups in whom levels of collagen deposition in the GALT appear comparable to the HIV-negative control group (shown in figure 1b of the paper).
Because lymphoid tissue fibrosis is correlated with CD4 T cell depletion, Schacker’s group has also used the SIV/macaque model to assess whether antifibrotic drugs can improve CD4 T cell reconstitution. The results of these experiments were published in a separate paper last September. Pirfenidone, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, was initially given prior to SIV challenge and then continued for 24 weeks in order to evaluate whether an effect could be demonstrated under idealized conditions. Results showed that fibrosis was prevented in treated macaques but not untreated controls, and the effect was independent of ART (which was administered to a subgroup of the pirfenidone recipients). CD4 T cell numbers were also preserved in peripheral blood and there was a 14% increase in lymphoid tissue CD4 T cells over the 24 weeks compared to an 8% decline in the untreated group.
In a follow up experiment, pirfenidone was started in combination with ART six weeks after SIV infection and a control group received ART alone. Treatment was again continued for 24 weeks. Lymphoid tissue fibrosis declined significantly in the pirfenidone group but continued to increase in animals receiving only ART. However no significant changes in blood or lymph node CD4 T cell numbers could be documented; the researchers suggest this might have been due to the relatively short duration of follow up.
Based on these encouraging findings, Schacker’s group has now begun a clinical trial of losartan in HIV-positive people on ART. Losartan is approved for the treatment of hypertension but also has antifibrotic activity. The study will test if losartan can reduce fibrosis and improve immune reconstitution, and also look for any effect on the size of the HIV reservoir. The trial is currently enrolling and potential participants from Minneapolis and Madison are actively being sought. Participation does require some altruistic dedication to scientific research because tissue sampling is an important part of the protocol and biopsies of inguinal lymph node and GALT will be conducted at baseline, 12 months and 30 months after enrollment. Some participants will also receive HPV vaccine immunizations during the study in order to evaluate if antifibrotic therapy can improve immune function. Detailed information about the trial is available in the clinicaltrials.gov listing.
J Infect Dis. (2014) doi: 10.1093/infdis/jiu586
First published online: October 24, 2014
Sanchez JL, Hunt PW, Reilly CS, Hatano H, Beilman GJ, Khoruts A, Jasurda JS, Somsouk M, Thorkelson A, Russ S, Anderson J, Deeks SG, Schacker TW.
HIV replication causes lymphoid tissue (LT) fibrosis which causes CD4 depletion. It is unknown if people who spontaneously control HIV replication have LT fibrosis. We measured LT fibrosis and CD4 cells in 25 HIV controllers, 10 non-controllers, 45 on therapy, and 10 HIV negative individuals. Controllers had significant LT fibrosis and CD4 depletion, similar to non-controllers, but the Berlin Patient (cured of HIV) had near normal LT. Thus, LT fibrosis occurs in all HIV-infected subjects and current therapy does not reverse it. Reversal of fibrosis during a curative intervention suggests that ongoing low-level virus production may maintain LT fibrosis.
J Infect Dis. (2014) doi: 10.1093/infdis/jiu519
First published online: September 22, 2014
Estes JD, Reilly C, Trubey CM, Fletcher CV, Cory TJ, Piatak M Jr, Russ S, Anderson J, Reimann TG, Star R, Smith A, Tracy RP, Berglund A, Schmidt T, Coalter V, Chertova E, Smedley J, Haase AT, Lifson JD, Schacker TW.
Even with prolonged antiretroviral therapy (ART), many human immunodeficiency virus-infected individuals have <500 CD4+ T cells/µL, and CD4+ T cells in lymphoid tissues remain severely depleted, due in part to fibrosis of the paracortical T-cell zone (TZ) that impairs homeostatic mechanisms required for T-cell survival. We therefore used antifibrotic therapy in simian immunodeficiency virus-infected rhesus macaques to determine whether decreased TZ fibrosis would improve reconstitution of peripheral and lymphoid CD4+ T cells. Treatment with the antifibrotic drug pirfenidone preserved TZ architecture and was associated with significantly larger populations of CD4+ T cells in peripheral blood and lymphoid tissues. Combining pirfenidone with an ART regimen was associated with greater preservation of CD4+ T cells than ART alone and was also associated with higher pirfenidone concentrations. These data support a potential role for antifibrotic drug treatment as adjunctive therapy with ART to improve immune reconstitution.