The Unenlarged Lymph Nodes of HIV-1–infected, Asymptomatic Patients with High CD4 T Cell Counts Are Sites for Virus Replication and CD4 T Cell Proliferation. The Impact of Highly Active Antiretroviral Therapy

Abstract

The efficacy of triple drug therapy for HIV-1 infection encourages its early use to prevent damage to the immune system. We monitored the effects of such therapy on 12 patients with 14–75-mo histories of minimal disease, i.e., CD4+ counts constantly >500/μl and little or no lymph node enlargement. In this way, we could first determine the extent of viral replication and immunoarchitectural changes in unenlarged nodes early in disease, and second follow the response to triple therapy in plasma and lymphoid tissue in tandem. As is known for lymph nodes with more advanced disease, the germinal centers showed productively infected T cells, i.e., CD4+CD1a−CD68− cells labeling intensely for HIV-1 RNA after in situ hybridization. The unenlarged nodes also showed extensive HIV-1 RNA retention on a well-preserved, follicular dendritic cell (FDC) network, and the follicles were abnormal. There were numerous CD8+ cells, many expressing TIA-1 granule antigen. Also, in contrast to normal follicles, CD4+ T cell proliferation was active, with marked increases in the number of cycling, Ki-67+CD4+CD45R0+ cells. After 28 d and 3 mo of therapy, productively infected T cells decreased dramatically and often were not apparent. The labeling of the FDC network for viral RNA also decreased, but not for gag protein. We conclude that HIV-1 replicates and accumulates in lymphoid organs before damage of the immune system, that at this stage of disease de novo production of T cells occurs in the lymphoid tissue, and that the infection is sensitive to triple drug therapy in both plasma and lymph nodes.

The Dominant Source of CD4+ and CD8+ T-Cell Activation in HIV Infection Is Antigenic Stimulation

“…The latter has been demonstrated using two different techniques. First, by determining the fraction of dividing cells through expression of the nuclear antigen Ki67 (12), it was shown that T-cell proliferation rate is increased maximally twofold to threefold in the CD4 + population, and sixfold to sevenfold in the CD8 population (13)(14)(15)(16). This limited increase in the division rate is consistent with results of studies that measured the replicative history of T cells by the average telomere lengths (17,18).…”

Persistence of Infectious HIV on Follicular Dendritic Cells

“…However, even with HAART, some virus remains after prolonged therapy, and levels below 10,000 copies of viral RNA per gram tissue may not be detected (11,34,35). A recent study indicated that even in the absence of detectable viral RNA, p24 protein remained on FDCs (36). This residual p24 may simply be trapped viral protein; however, we reason that it may also represent virus on FDCs that is below the level of detection by in situ hybridization.…”

IL-4 and a glucocorticoid up-regulate CXCR4 expression on human CD4+ T lymphocytes and enhance HIV-1 replication

“…The plasma virions were estimated to have a mean life-span of 0.3 days (t 1/2 ϭ 0.24 days), and the estimated average total HIV-1 production was 10.3 ϫ 10 9 virions/day. Recent findings provided further evidence for such a simple steady-state model in that the enlarged lymph nodes of HIV-1-infected, asymptomatic patients with high CD4 ϩ T cell count were identified as sites for virus replication and CD4 ϩ T cell proliferation [33]. Therefore, the HIV-1 infection process is not only a key event as the starting point in AIDS pathogenesis, but also an essential event for the progression of the disease.…”