Correlates of latent and productive HIV type-1 infection in tonsillar CD4 ⁺ T cells

Abstract

Correlates of virus load and characteristics of virus-producing cells in tonsillar tissue were investigated. Our results suggest that when less than 1:100 tonsillar CD4 ؉ T cells from individuals infected with HIV type-1 (HIV-1) contain replication competent provirus, the level of CD4 ؉ T cells in tonsils is comparable to that observed in uninfected individuals. Virus load at or above this level was associated with low CD4 cell numbers in tonsillar tissue. Only a few percent of all infected T cells in tonsillar tissue were active virus producers, with minor differences observed between individuals. Plasma viremia was found to correlate with infectious virus load in tonsillar tissue. With less than 1:1,000 of CD4 cells in lymphoid tissues being involved in active virus production, direct cytopathic effect by HIV-1 on infected CD4 cells is unlikely to fully explain the immunodeficiency seen in AIDS.HIV type-1 (HIV-1) predominantly infects T cells that express CD4 (1). However, through years of clinically latent HIV-1 infection the proportion of CD4 ϩ T cells in blood carrying replication competent provirus is typically less than 1:1,000 (1, 2). More recent studies have suggested higher viral loads in lymphoid tissues (3). Still, the proportion of HIV-1-producing cells has been considered by many to be insufficient to fully explain the overall loss of CD4 ϩ T cells suggested by the low levels of CD4 ϩ T cells in blood (4). New data estimating a production of up to 10 10 HIV-1 particles and a continuously high turnover of CD4 ϩ T cells has profoundly affected current thinking on the immunopathogenesis of AIDS (5-8). These estimations were made by measurement of the concentration of CD4 cells in peripheral blood and virions in plasma after in vivo treatment with potent inhibitors of HIV-1 replication (5-7). However, only approximately 2% of all lymphocytes are found in peripheral blood; the majority of lymphocytes are located in lymphoid tissues. Thus, studies of cellular changes and virus load in lymphoid tissues are required to fully understand the forces driving the development of AIDS. The palatine tonsils, containing lymphoid tissue with characteristics similar to both lymph node tissue and gut-associated lymphoid tissue, may yield biopsy material suitable for such studies. Examining biopsies of tonsillar tissue from HIV-1-infected individuals at different clinical stages of infection, we have recently shown that in tonsillar tissue from asymptomatic HIV-1-positive individuals, CD4 ϩ T cells are maintained at levels similar to those observed in uninfected controls, despite reduced CD4 ϩ T cell counts in blood (9).The present study focuses on correlates of virus load in tonsillar tissue. We show evidence suggesting that as long as the proportion of provirus-containing CD4 cells is below 1:100, the level of CD4 cells in lymphoid tissues remains relatively unaffected. Virus load at or above this threshold of infection was associated with low levels of tonsillar tissue CD4 ϩ T cells. Moreover, we show that o...

Gag-Specific CD8+ T Lymphocytes Recognize Infected Cells before AIDS-Virus Integration and Viral Protein Expression

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Dendritic Cells Infected withvpr-Positive Human Immunodeficiency Virus Type 1 Induce CD8+T-Cell Apoptosis via Upregulation of Tumor Necrosis Factor Alpha

“…Studies using a large cohort of HIV-1 patients at various stages of disease showed that a significantly higher degree of apoptosis of T cells correlated with rapid progression of the disease (17). Apoptosis occurs primarily in uninfected bystander cells, mainly in CD4 ϩ T cells and CD8 ϩ T cells in tonsillar tissues (46) and T cells, B cells, and DC in the lymph nodes (33) in vivo. These apoptotic cells have been shown to exceed the numbers of productively infected cells, further suggesting the occurrence of bystander cell death (11).…”

Residual Human Immunodeficiency Virus Type 1 Infection in Lymphoid Tissue during Highly Active Antiretroviral Therapy: Quantitation and Virus Characterization

“…1,4,5 However, in lymphoid tissue, the frequency of CD4 1 T cells with replication-competent proviral DNA is less than 1% during the asymptomatic period 1,4,5 and less than 1 in 1000 CD4 1 T cells are actually involved in active virus replication. 5,6 The current assumption is that HIV-1 virions trapped in the follicular dendritic cell (FDC) network account for the major part of HIV-1 RNA found in lymphoid tissue in chronic HIV-1 infection. [1][2][3][6][7][8] However, it is debatable whether FDC-associated virions dominate over intracellular viruses in lymphoid tissue.…”

“…[15][16][17][18][19][20] Whereas a high baseline 21,22 and week 24 posttherapy plasma HIV-1 RNA level 23 is predictive of clinical progression, a substantial initial decline in plasma HIV-1 RNA after therapy is inversely correlated with the probability of rebound plasma viremia. 24 Although HIV-1 viral load in plasma and blood lymphocytes correlates with virus replication in lymphoid tissue, 5,[15][16][17] little is known about the predictive value of viral parameters in lymphoid tissue.…”