HIV-1 Infection of CD4+ T Cells in the Gut

Hopkins HIV Report 2006 May; 18(3):8

Megan Wind-Rotolo Ph.D. and Joel N. Blankson M.D., Ph.D.
Johns Hopkins

Clinicians and researchers have used peripheral blood as a convenient way of obtaining information on CD4 cell counts and the extent of viral replication in HIV-infected individuals. However, it should be noted that only 2% of the total body store of lymphocytes circulate in the peripheral blood; the other 98% reside in lymphatic tissue scattered throughout the body. Gut-associated lymphatic tissue (GALT) represents the single largest pool of lymphocytes, and as such, it is not surprising that it is a major target for HIV infection. In the past few years several major observations have been made regarding GALT. First, there is a massive depletion of GALT CD4 cells during primary infection. These cells are affected to a much higher degree than CD4 cells in the peripheral blood [Veazey R, et al. Science. 1998 Apr 17;280(5362):427-31, Brenchley JM, et al. J Exp Med. 2004 Sep 20;200(6):749-59]. Furthermore, there is little or no reconstitution of these cells after the initiation of HAART in chronically infected patients [Guadalupe M, et al. J Virol. 2003 Nov;77(21):11708-17, Mehandru S, et al. J Exp Med. 2004 Sep 20;200(6):761-70]. Finally, HIV-1 DNA and RNA can be detected in rectal biopsies from patients on HAART with undetectable plasma viral loads, suggesting that GALT CD4 cells can serve as a reservoir for HIV infection [Anton PA, et al. AIDS. 2003 Jan 3;17(1):53-63]. At this year’s CROI there were numerous oral presentations regarding this interesting topic.

Brenchley and colleagues determined the frequency of HIV-infected CD4 cells in the gut of HIV-infected patients who had been on HAART for up to 3 years [Brenchley J, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 38]. They found that on average the frequency of infection of GALT CD4 cells was 10 times higher than that of CD4 cells from blood. Memory CD4 cells from the gut were also shown to be capable of producing virus, and while there was no direct evidence of active replication, it was concluded that gut depletion is likely caused by ongoing infection of local CD4 cells. In addition, few HIV-specific CD8 cells were found in the gut compared to the blood, indicating that the proposed ongoing viral replication in GALT is associated with a lack of local HIV-specific immunity.

Baker and colleagues also measured the frequency of CD4 cells in GALT and showed that the percentage of CD4 cells in this region is 50% lower in HIV-infected patients compared to non-infected controls [Baker J, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 41]. Interestingly, while there was a significant increase in peripheral CD4 cell counts after 6 months of HAART, there was no increase in the percentage of GALT CD4 cells. This is more evidence that CD4 cell depletion in the gut may not be reversible in chronically infected patients. The effect of depletion of gut CD4 cells is unknown, but there was an incidental finding of intestinal polyps in 6/31 relatively young HIV-infected patients, including 1 precancerous lesion and 1 case of cancer.

HIV-infected patients who started HAART within 3 weeks of infection were shown to be able to repopulate memory CD4 cells in the gut [Dandekar, et al. Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 39]. The initiation of HAART was also associated with a lower frequency of infection of GALT CD4 cells. The expression of genes in the gut of patients who started HAART early was compared with that of patients who started HAART at later time points. Those who were started HAART early showed lower expression of inflammation and cellular activation genes and increased expression of mucosal repair and regeneration genes. These results led to the conclusion that the disruption of the gut microenvironment causes the depletion of CD4 cells.

Having shown a high frequency of infection of GALT CD4 cells, Douek and colleagues looked at other mucosal sites as well [Douek D, Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 166]. Massive depletion of CD4 cells in the lung has previously been described in pathogenic SIV infection of Rhesus macaques [Picker LJ, et al. J Exp Med. 2004 Nov 15;200(10):1299-314). The investigators have begun to study the effect of HIV on CD4 cells of the lung by analyzing cells from brocheoalveolar lavage of HIV-uninfected and HIV-infected patients. Preliminary data indicate that the pattern seen at this site differs markedly from that observed in the GALT. There is no depletion of CD4 cells associated with HIV infection; instead, an increase in the number of both CD4 and CD8 cells is seen. In contrast to the high frequency of infected cells in the GALT, the frequency of infection of lung CD4 cells is relatively low (comparable to the frequency of infection of peripheral blood CD4 cells). In addition, HIV-specific CD8 and CD4 cell responses are preserved at this site, and it was proposed that this local immunity may explain the low cellular viral loads and the preservation of normal CD4 cell counts.

What are the clinical consequences of CD4 cell infection in GALT? While it appears that the poor reconstitution of CD4 cells at this site is not associated with major GI symptoms in most patients on HAART, the relatively high frequency of pathology seen by Baker and colleagues is concerning [Baker J, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 41]. Confirmatory studies in larger cohorts of patients are needed. If reconstitution of GALT CD4 cells is important, then the work of Dandekar and colleagues [Guadalupe M, et al., Conf Retrovir Opportunistic Infect 2006 Feb 5-8;13:abstract no. 39] would suggest that there is a major advantage to early treatment with HAART. The GI tract appears to be the major target in primary infection; therefore, it follows that preventative vaccines will need to induce strong mucosal immunity in order to be effective. The high frequency of infected cells in the GALT has been interpreted by some investigators to be evidence of ongoing replication in patients on HAART. If this is correct, it could potentially explain treatment failure in some patients. This issue clearly needs to be definitively addressed, and tissue drug levels at this site should be measured. Finally, investigators working on eradication of HIV infection have based their models on the rate of decay of latently infected cells in the peripheral blood. Nothing is known about the half-life of infected cells in GALT. As these cells and infected cells from other anatomical reservoirs are studied, major revisions in these models will likely be needed.

2006-05-10
HHR-2006-05-03

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