HIV Never Sleeps: Evidence to Support Early Antiretroviral Treatment Free

The year 1993 marked 12 years after the description of AIDS (1), 10 years after the first description of what became known as HIV (2), and 9 years after HIV was shown to be the cause of AIDS (3, 4). Despite this progress, debates led by virologist Peter Duesberg and others were still ongoing in 1993 regarding whether AIDS was caused by HIV (5), and for those scientists who accepted AIDS is caused by HIV, a critical question was, how can the paucity of HIV in blood explain the profound immune destruction in AIDS (6)? In March 1993, Pantaleo et al. (7) published a seminal paper addressing this latter question using PCR technology to analyze simultaneously the presence of HIV in blood and immune tissues and, in doing so, added key data that reinforced the pathogenic role of HIV in AIDS.

The team from the Fauci laboratory (7) at the National Institute of Allergy and Infectious Diseases studied 12 persons living with HIV who were in early, intermediate, or late stages of HIV infection. They demonstrated localization and sequestration of HIV-infected CD4⁺ T cells in lymphoid tissues early in HIV infection, thus explaining the dearth of infected T cells in blood in previous studies. In early and intermediate stages of infection, expression of HIV appeared to be low in blood, because sensitive PCR assays to detect low copy numbers of virus RNA were not widely available at that time. In contrast, high levels of HIV-specific RNA were detected by in situ hybridization in lymphoid tissue mononuclear cells, requiring protease treatment of tissue sections for full viral gene identification, which suggested Ab coating of virions in situ (7). Late-stage AIDS showed disruption of the follicular dendritic cell network in lymph node germinal centers, indicating a diminished ability to trap virions, leading to increased HIV in blood late in disease.

There were multiple key findings in the paper by Pantaleo et al. (7) that influenced the thinking of both the HIV pathogenesis and the HIV therapeutic fields. First, this and other similar papers (7–9) resolved the question of whether there was sufficient virus in HIV-infected individuals to cause the immune destruction–associated immunodeficiency of clinical AIDS. The finding of high levels of HIV-infected cells in lymphoid tissues both provided for virus-mediated mechanisms of immune destruction and refuted the claims of those who doubted a retrovirus cause of AIDS (5). In the March 25, 1993, issue of Nature, in which the paper by Pantaleo et al. (7) was published, John Maddox (10) wrote an editorial that Peter Duesberg’s view that HIV was not the cause of AIDS was implausible because of the papers of Pantaleo et al. (7) and Ashley Haase’s (8) team, who found similarly high levels of HIV in immune tissues. Indeed, Maddox (10) advised Duesberg to “admit the likelihood that he is mistaken.”

Second, the Pantaleo et al. (7) study demonstrated mechanisms responsible for reduced viral load in peripheral blood early in infection. These mechanisms involved a combination of mechanical filtering and trapping of virions by immune tissue germinal center follicular dendritic cells and the sequestration of infected CD4⁺ T cells in hyperplastic lymph nodes (7). Pantaleo et al. (7) not only showed multiple HIV-infected cells in lymph nodes but also in adenoids and tonsils, demonstrating HIV dissemination throughout the immune system.

A seminal point made in the paper was the finding of active viral replication in immune tissues during the clinically latent stage of HIV infection. The authors noted that “therefore a state of true microbiological latency does not exist during the course of HIV infection.…HIV disease is active and progressive even when there is little evidence of disease activity…” (7). As highly effective antiretroviral treatment (ART) evolved from 1995 to 1997, the work by Pantaleo et al. (7) and in related papers (8, 9) suggested clinical use of ART early on in HIV infection rather than waiting for a decline in CD4⁺ T cell numbers (11).

The paper by Pantaleo et al. (7) spurred the Fauci group and others to subsequently explore the effect of ART on the latent pool of infected CD4⁺ T cells and to demonstrate the extreme difficulty in eliminating these cells (12). The concepts in this early work, in turn, led to a number of provocative strategies for elimination of the latent pool of HIV-infected CD4⁺ T cells that are currently being investigated (13, 14).

Finally, the Pantaleo et al. (7) paper planted the seed for a program to meet the need for early treatment of HIV infection in Africa and on a more global scale, which became manifest in 2003 as the President’s Emergency Plan For AIDS Relief (PEPFAR), of which Anthony Fauci was one of the main architects (15). Therefore, one can trace a thread from the Pantaleo et al. (7) paper in Nature in 1993 to the creation of the PEPFAR program, which provided for universal treatment of persons with HIV regardless of the stage of their infection, to current times where it is estimated that PEPFAR has saved the lives of >20 million individuals from AIDS-related death.

In summary, the concepts in the Pantaleo et al. (7) paper in Nature on the presence of HIV⁺ cells in immune tissues from the earliest to the advanced stages of infection were not only seminal for the HIV pathogenesis and the HIV therapy fields but also influenced both public health officials and political leaders to develop highly effective global programs to counter the AIDS epidemic.