Peripheral lymphocytes of clinically non‐progressor patients harbor inactive and uninducible HIV proviruses

Abstract

The HIV viral burden and RNA expression in a selected group of infected, clinically non-progressor patients were investigated. Five fast-progressor patients and 10 AIDS cases were included as controls. The HIV viral load was investigated by semiquantitative polymerase chain reaction (PCR) in adherent macrophages and in genomic and extragenomic fractions of lymphocytes. HIV DNA was not found in macrophages in the non-progressor subjects, was weakly positive in 2 of 5 fast-progressors and strongly positive in most of the AIDS patients. The number of HIV proviruses found in lymphocytes of the non-progressor subjects varied from 5 to 160 copies/microgram DNA, values ten times lower than those recorded in fast-progressors and AIDS patients. The extragenomic HIV DNA (2 LTR forms) was absent or barely detectable in the lymphocytes from non-progressors and abundant in the other groups. HIV RNA was not found in the lymphocytes of all non-progressors. This may indicate that a latent state of HIV provirus exists in the lymphocytes of these subjects. To investigate this point, cultivation and stimulation with PHA (phytohemoagglutinin) and PMA (phorbol 12-myristate 13-acetate) of lymphocytes from these subjects were attempted but after 6 days HIV RNA (RT-PCR for gag region) was still absent or barely detectable in these patients. There are no other reports of the absence of HIV provirus induction in lymphocytes from infected individuals. If confirmed in a larger number of patients, such non-inducibility might serve as a predictor marker of progression of the disease.

HIV-Specific CD4+ T Cells May Contribute to Viral Persistence in HIV Controllers

“…Although viruses from HIV controllers may be somewhat less fit than viruses from viremic individuals [30,31], replication-competent virus can be isolated from many controllers and some have been infected with highly pathogenic viruses from individuals with AIDS [32][33][34]. Despite infection with replication-competent viruses and having susceptible CD4 1 T cells, HIV controllers maintain much lower cell-associated DNA levels than do HIV-infected individuals maintaining treatment-mediated viral suppression [17][18][19]. These exceptionally small cellular reservoirs in HIV controllers have been largely attributed to a highly potent cytotoxic HIV-specific CD8 1 T cell response, observable in the majority of these individuals [1][2][3][4][5][6][7][8][9][10][11][12][13].…”

“…It has long been known that HIV-specific CD4 1 T cells are more likely to be infected with HIV than non-HIV-specific CD4 1 T cells [20]. It is worth carefully considering this point in the context of HIV controllers because-as a group-they harbor extremely high frequencies of HIV-specific CD4 1 T cells while maintaining extremely low proviral HIV DNA levels [3,5,6,[17][18][19]. Taken together, these observations might suggest that the latent reservoir in HIV controllers is more highly concentrated in the HIV-specific CD4 1 T cell population than in most other HIV-infected individuals.…”

“…There may also be negative inflammatory consequences to the immunologic control of HIV infection in HIV controllers, including systemic immune activation-occasionally contributing to significant decreases in the CD4 1 T cell count and to AIDS-and atherosclerosis [15,16]. Finally, despite potent HIVspecific T cell responses and relatively small reservoirs of latently infected cells, no HIV controller has ever completely eradicated HIV [17][18][19].…”

Infrequent Recovery of HIV from but Robust Exogenous Infection of Activated CD4+T Cells in HIV Elite Controllers

“…Interestingly, long-term non-progressors exhibit not only reduced levels of plasma viral replication, but also have lower numbers of CD4+ T-cells with integrated HIV provirus compared to individuals with fast-progressive disease and AIDS [17, 18]. This finding suggests that either: a) these individuals have a unique capacity to control viral replication actively over time, b) they are infected with viruses that do not replicate, and/or c) these individuals possess CD4+ T-cells with a unique ability to resist HIV-infection.…”

Rapid and sensitive detection of cell-associated HIV-1 in latently infected cell lines and in patient cells using sodium-n-butyrate induction and RT-PCR

“…However, the same technique applied to human non-progressor patient PBMCs has not been successful [Garbuglia et al, 1995]. Therefore, it was of considerable interest to us to be able to detect viral genome from a cell population with a low infection rate, i.e., PBMCs as opposed to clonal cell lines such as lymphocytic ACH-2 cells where 100% of cells are infected with HIV genome.…”