Virus Burden in Long-Term Survivors of Human Immunodeficiency Virus (HIV) Infection Is a Determinant of Anti-HIV CD8+ Lymphocyte Activity

Abstract

Persons infected with human immunodeficiency virus (HIV) for > 8 years were studied to delineate virologic and immunologic attributes of long-term survival. Whereas those with 300-700 CD4+ cells/microL often had circulating cytotoxic T lymphocytes (CTL) against HIV antigens, those with > 1000 CD4+ cells/microL did not. The subjects with > 1000 CD4+ cells/microL had low virus burden, low levels of Gag-specific CTL precursors, and minimal CD8+ cell activation. Overall, elevated levels of CD8+ cells, CD38 antigen expression on CD8+ cells, and anti-HIV functions were correlated with increased virus burden, provirus load, and HIV plasma RNA levels. A factor that suppressed HIV replication was spontaneously secreted from CD8+ cells of most subjects but not from those with high CD4+ cell counts. CD8+ cell activities, therefore, may reflect chronic viral stimulation of the immune system. Long-term survivors with high levels of CD4+ cells maintained control of viral replication but lacked the CD8+ cell activities.

Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors

“…These numbers are ϳ3-15 times the number previously estimated by enzyme-linked immunospot or tetramer analysis (18, 40, 47, 52-54). In some cases, this percent approaches the total number of CD3 ϩ CD38 ϩ T cells previously believed to be mostly due to bystander activation in infected patients (21). This study includes a unique cohort of LTNPs that has been infected Ͼ13 years, has strong proliferative responses to HIV Ags, and maintains plasma virus levels Ͻ50 copies/ml.…”

“…It has previously been proposed that patients that maintain effective restriction of HIV replication do so because of greater HIV-specific CD8 ϩ T cell responses. However, previous studies have not consistently demonstrated a significant correlation between levels of plasma virus and CD8 ϩ T cell responses measured in vitro (7,8,10,21,37,55,56). It has been further suggested that significant correlations between plasma virus levels and measures of HIV-specific CD8 ϩ T cell responses were not detected because the assays used require in vitro stimulation, are poorly reproducible, or are not reliably quantitative.…”

“…Previous studies have identified patients with low levels of HIV-specific CD8 ϩ T cell responses in end stage disease (8,54). Conversely, low responses have also been observed by a variety of methods in some LTNPs with very low virus loads similar to patients 5 and 6 (8,21,40,54) suggesting the measured CD8 ϩ T cell responses may be dependent on virus replication in such patients. Thus, the results of such correlations might be dramatically affected by inclusion of patients at either extreme of HIV infection.…”

TCRγδ+ and CD161+ Thymocytes Express HIV-1 in the SCID-hu Mouse, Potentially Contributing to Immune Dysfunction in HIV Infection

“…Virus stocks were prepared from 24-h harvests of supernatants from CEM cells (CCRF-CEM) infected with virus derived from COS cells electroporated with plasmid pNL4-3 (39). The nonsyncytium-inducing CCR5-tropic molecular clone HIV-1 JR-CSF (JR-CSF) stocks were prepared from 24-h harvests of supernatants from stimulated PBMC infected with the supernatant of COS cells electroporated with plasmid pYKJR-CSF (40) and expanded in stimulated PBMC or in a cryopreserved pool of purified activated allogenic CD4 ϩ cells prepared as described in the literature (41). Briefly, allogenic CD4 ϩ cells from three normal donors were individually purified by capture in CD4 mAb-coated tissue culture flasks (Applied Immunosciences, Santa Clara, CA) and activated by stimulation with Ab to CD3 (OKT3; Ortho Biotech, Raritan, NJ) at 200 ng/ml and with rIL-2 (5000 U/ml) for 5 days.…”

Influence of polypeptide size and intracellular sorting on the induction of epitope-specific CTL responses by DNA vaccines in a mouse model

“…A strong antiviral cytotoxic activity has been shown to correlate timely with the clearance of viremia in primary infection [5,6]. Furthermore, Gag-specific T helper cell and CTL responses seem to correlate inversely with the viral load [7,8].…”