Kinetics of CD4+ T cell repopulation of lymphoid tissues after treatment of HIV-1 infection

Abstract

Potent combinations of antiretroviral drugs diminish the turnover of CD4؉ T lymphocytes productively infected with HIV-1 and reduce the large pool of virions deposited in lymphoid tissue (LT). To determine to what extent suppression of viral replication and reduction in viral antigens in LT might lead correspondingly to repopulation of the immune system, we characterized CD4؉ T lymphocyte populations in LT in which we previously had quantitated viral load and turnover of infected cells before and after treatment. We directly measured by quantitative image analysis changes in total CD4؉ T cell counts, the CD45RA؉ subset, and fractions of proliferating or apoptotic CD4؉ T cells. Compared with normal controls, we documented decreased numbers of CD4؉ T cells and increased proliferation and apoptosis. After treatment, proliferation returned to normal levels, and total CD4؉ T and CD45RA؉ cells increased. We discuss the effects of HIV-1 on this subset based on the concept that renewal mechanisms in the adult are operating at full capacity before infection and cannot meet the additional demand imposed by the loss of productively infected cells. The slow increases in the CD45RA؉ CD4؉ T cells are consistent with the optimistic conclusions that (i) renewal mechanisms have not been damaged irreparably even at relatively advanced stages of infection and (ii) CD4؉ T cell populations can be partially restored by control of active replication without eradication of HIV-1.

Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4 + and CD8 + T cell turnover in HIV-infected patients

“…Our results are consistent with a number of studies finding 2-to 6-fold higher CD4 ϩ and CD8 ϩ T cell proliferation in subjects with HIV or simian immunodeficiency virus infection (9)(10)(11)(12)(13)(15)(16)(17)(18)(19), suggesting a global activation of the immune system caused by HIV͞simian immunodeficiency virus replication. Our longitudinal studies showing declines in both fractional and absolute T cell proliferation after initiation of HAART and increases after cessation of HAART in parallel to changes in viral load clearly show that T cell proliferation is directly correlated with viral replication.…”

“…Studies of lymphocyte turnover derived through analysis of immediate changes in CD4 ϩ T cell counts in the blood after highly active antiretroviral therapy (HAART) also led to estimates of high rates of CD4 turnover (2)(3)(4), although others have suggested that lymphocyte redistribution may be the major cause for CD4 increases immediately after HAART (5)(6)(7)(8). Measurements of lymphocyte proliferation using Ki-67, BrdUrd, and 2 H-glucose have yielded varying results (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19); however, the general consensus is that T cell proliferation is increased in HIV͞simian immunodeficiency virus-infected subjects. Variations in these studies may be caused by the difference in sample numbers, cross-sectional versus longitudinal studies, patient cohort composition, and whether one is measuring the absolute or fractional level of cell division.…”

Persistence of HIV-1 structural proteins and glycoproteins in lymph nodes of patients under highly active antiretroviral therapy

“…The effects of this therapy are manifested by a strong suppression of viral replication in the peripheral blood and in lymphoid tissue in individuals infected with HIV-1 (11,12). As a result, CD4ϩT cell counts increase, T cell activation decreases, and antigen-specific and nonspecific T cell function improves (13)(14)(15)(16)(17)(18). Similarly, B cell responses are normalized, although this reversal of profound alteration of immune system is a slow and incomplete process in a number of long-term treated patients (19)(20)(21)(22).…”

Erratum for vol. 95, p. 3635

“…21,22 This is suggested by studies in patients with TCD due to HIV infection showing increased susceptibility of T cells to apoptosis with restimulation in vitro [23][24][25][26][27] and by direct labeling studies in vivo. [28][29][30] Although these observations could potentially relate to direct or indirect effects of HIV, similar results have been observed in T-cell-depleted hosts after intensive chemotherapeutic regimens 20 and after stem cell transplantation, 31 suggesting that increased susceptibility to cell death is a common phenomenon in regenerating T-cell populations. Thus, a propensity for programmed cell death in peripherally expanding T-cell populations may also limit the capacity of peripheral expansion to restore host immune competence.…”