Gut Is Hideout For HIV Despite Long-term Therapy
Even with effective anti-HIV therapies, doctors still have not been able to eradicate the virus from infected individuals who are receiving such treatments, largely because of the persistence of HIV in hideouts known as viral reservoirs. One important reservoir is the gut, where HIV causes much of its damage due to the large number of HIV target cells that reside there. These cells, known as CD4+ T cells, are largely contained in lymph nodes and patches of lymphocytes that collectively are called gut-associated lymphoid tissue, or GALT.
Because of the importance of the gut to HIV disease, scientists hoped that long-term treatment with antiretroviral drugs could eradicate HIV from the GALT. A new NIAID study1 has found that this goal seems unlikely with current antiretroviral drugs.
Tae-Wook Chun, Ph.D., of the NIAID Laboratory of Immunoregulation (LIR), Anthony S. Fauci, M.D., LIR chief and NIAID director, and their colleagues intensively studied eight patients receiving effective antiretroviral therapy for up to 9.9 years. In each of these of these individuals, therapy had consistently kept their blood levels of HIV at undetectable levels. Sensitive tests, however, detected the persistence of HIV as well as lowered CD4+ T cell levels in the GALT that did not completely rebound in response to therapy. Levels of virus were higher in the GALT than in immune cells in the blood, where HIV also was consistently found.
In addition, the scientists found evidence of cross infection between the GALT and the lymphocytes in the blood, suggesting that one reason the virus persists in the blood is because of ongoing cycles of replication in the GALT. The authors conclude that any possibility of further lowering or eliminating viral reservoirs likely will require more powerful drug regimens to stop the low levels of ongoing viral replication originating in the GALT. The development of such regimens is an important goal of NIAID-supported research.
A second study from the Fauci laboratory, conducted by Susan Moir, Ph.D., and her colleagues2 provides additional insights into the effects of antiretroviral therapy on the HIV disease process.
In most HIV-infected individuals, the virus replicates at high levels and CD4+ T-cell numbers decline. These two factors also strongly affect B cells, the cells of the immune system that make antibodies and help protect against infection. Dr. Moir and her colleagues demonstrated that prior to treatment with antiretroviral therapy, B-cell numbers in the blood of HIV-infected individuals who have been infected for several years are low, and the B cells also include several dysfunctional subsets.
After one year of effective treatment with antiretroviral therapy, B-cell numbers returned to normal, and several of the dysfunctional subsets also normalized. However, those B-cells that provide long-term protection against infection–so-called memory B cells–did not return to normal levels. Dr. Moir notes that these findings strengthen the notion that while antiretroviral therapy improves many aspects of immune function in HIV-infected individuals, important deficiencies remain, especially in individuals who wait several years before initiating therapy. More studies are needed to determine whether early initiation of antiretroviral therapy helps restore the immune system more completely.
J Infect Dis. 2008 Feb 8 [Epub ahead of print]
Persistence of HIV in Gut-Associated Lymphoid Tissue despite Long-Term Antiretroviral Therapy.
Chun TW, Nickle DC, Justement JS, Meyers JH, Roby G, Hallahan CW, Kottilil S, Moir S, Mican JM, Mullins JI, Ward DJ, Kovacs JA, Mannon PJ, Fauci AS.
1Laboratory of Immunoregulation, 2Biostatistical Research Branch, 3Laboratory of Host Defense, 4Division of Clinical Research, National Institute of Allergy and Infectious Diseases, 5Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda, Maryland; 6Department of Microbiology, University of Washington, Seattle; 7Dupont Circle Physicians Group, Washington, DC.
Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.
J Infect Dis. 2008 Feb 1 [Epub ahead of print]
Normalization of B Cell Counts and Subpopulations after Antiretroviral Therapy in Chronic HIV Disease.
Moir S, Malaspina A, Ho J, Wang W, Dipoto AC, O’Shea MA, Roby G, Mican JM, Kottilil S, Chun TW, Proschan MA, Fauci AS.
1Laboratory of Immunoregulation, 2Division of Clinical Research, and 3Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.
Untreated human immunodeficiency virus (HIV) disease leads to abnormalities in all major lymphocyte populations, including CD4(+) T cells, CD8(+) T cells, and B cells. However, little is known regarding the effect of antiretroviral therapy (ART)-induced decrease in HIV viremia on B cell numbers and subpopulations.
We conducted a longitudinal study to evaluate changes in B cell numbers and subpopulations that occur during the course of 12 months of effective ART in a group of individuals with chronic HIV infection. Results. @nbsp; ART-induced decrease in HIV viremia was associated with a significant increase in B cell counts, similar to increases in CD4(+) T cell counts yet distinct from the lack of increase in CD8(+) T cells. The increase in B cell counts was accompanied by a significant decrease in the frequency of apoptosis-prone B cell subpopulations, namely mature activated and immature transitional B cells, which are overrepresented in untreated HIV disease. The increase in B cell counts was reflected by a significant increase in naive and resting memory B cells, both of which represent populations that are essential for generating adequate humoral immunity.
Normalization of B cell counts and subpopulations may help to explain the improvement in humoral immunity reported to occur after an ART-induced decrease in HIV viremia.