HIV-1 latency and reservoir

In human immunodeficiency virus type 1 (HIV-1)-infected patients, replication-competent virus persists in a long-lived reservoir comprised of resting CD4+ T lymphocytes latently infected with HIV-1[6]. It is becoming clear that viral reservoirs established early in […]

In human immunodeficiency virus type 1 (HIV-1)-infected patients, replication-competent virus persists in a long-lived reservoir comprised of resting CD4+ T lymphocytes latently infected with HIV-1[6].
It is becoming clear that viral reservoirs established early in the infection not only prevent sterilizing immunity but also represent a major obstacle to curing the infection with the potent antiretroviral drugs currently in use [2, 5].
In HIV-1-infected individuals, the presence of unintegrated viral genome in resting CD4+ T lymphocytes is sustained by the fact that latently HIV-1-infected resting CD4+ T cells treated early with highly active antiretroviral therapy (HAART) shows a biphasic decay[6]. After an initial fast decay that wipes out the majority of circulating viruses in 1–2 weeks [2, 6], HIV-1-infected resting CD4+ T cells declines at a slower rate, reflecting the turnover of a longer-lived viral reservoir in infected cell population. The two phases of this decay are related to the two different forms of latency and support models of pre- and post integration latency [6].
The mechanisms of viral persistence are best considered in the context of the dynamics of viral replication in vivo. In infected individuals, viral production is a dynamic process involving continuous rounds of infection of CD4+ T lymphocytes with rapid turnover of both free virus and virus-producing cells that have a half-life of 1–2 days [2, 5].

Mechanisms of viral persistence

In untreated patients, there is an active viral replication with continual infection of resting T cells, leading to a labile pool of cells in the preintegration phase of latency. When HAART is initiated, viral replication ceases, probably leading to the rapid decay of this labile reservoir. However, the persistence of preintegrated forms of HIV-1 could be explained by the de novo infection of resting CD4+ T cells due to residual viral replication. Unintegrated viral reservoir could provide an inducible and functional reservoir for HIV-1 in untreated as well as in patients with sustained response to HAART [6].
Persistent low levels of viral replication are felt to be the major factor involved in the maintenance of the reservoir of HIV-1, as reflected by the frequency of CD4+T cells carrying HIV-1 proviral DNA in patients whose plasma viremia has been suppressed by HAART to below the level of detection of standard assays[3].
There are several potential cellular and anatomical reservoirs for HIV-1 that may contribute to long-term persistence of HIV-1. These include infected cell in the central nervous system and the male urogenital tract. However, the most worrisome reservoir consists of latently infected resting memory CD4 (+) T cells carrying integrated HIV-1 DNA [4, 5].

Longitudinal studies suggest that the size of this reservoir remains stable in most patients despite long-term treatment [1]. The extraordinary stability of the reservoir may reflect gradual reseeding by a very low level of ongoing viral replication and/or mechanisms that contribute to the intrinsic stability of the memory T cell compartment [5].

Cellular reservoirs for HIV-1 could also be CD4+ T lymphocytes not fully activated, which carry the integrated provirus in a non-replicative state until the activation process is complete, dendritic cells (DCs) may also delay the release of infectious virus, since they are not permissive for HIV infection but can carry the virus trapped on their surfaces [2].

It has been established that the reservoir of infected CD4+ T cells in the peripheral blood, as determined by the number of cells carrying HIV-1 proviral DNA, is maintained by ongoing viral replication, even at very low levels [3]

In CD4+ T lymphocytes, the replicative state of the virus is dependent upon the cell cycle of the host cell [2]. Most of the latent virus in resting CD4 (+) T cells is found in cells of the memory phenotype. The half-life of this latent reservoir is extremely long (44 months). At this rate, eradication of this reservoir would require over 60 years of treatment. Thus, latently infected resting CD4(+) T cells provide a mechanism for life-long persistence of replication-competent forms of HIV-1, rendering unrealistic hopes of virus eradication with current antiretroviral regimens [1,2,5].
A more stable form of latency occurs in CD4+ T cells that carry an integrated provirus. In principle, since integration requires T cell activation to allow efficient reverse-transcription and nuclear import of the pre-integration complex,post-integration latency can result only from the return of an infected activated T cell to a quiescent state [2].

1.Christian T. Ruff, Rebekah Zinn, Robert F. Siliciano and Deborah Persaud . Persistence of Wild-Type Virus and Lack of Temporal Structure in the Latent Reservoir for Human Immunodeficiency Virus Type 1 in Pediatric Patients with Extensive Antiretroviral Exposure JOURNAL OF VIROLOGY, Sept. 2002, p. 9481–9492

2.Alessandro Marcello, Latency: the hidden HIV-1 challenge
Retrovirology 2006, 3:7

3. Tae-Wook Chun, J. Shawn Justement,Colin Kovacs, and Anthony S. Fauci Relationship between the Size of the Human Immunodeficiency Virus Type 1(HIV-1) Reservoir in Peripheral Blood CD4+ T Cells and CD4+:CD8+ T Cell Ratios in Aviremic
HIV-1–Infected Individuals Receiving Long-Term HighlyActive Antiretroviral Therapy. The Journal of Infectious Diseases 2002;185:1672–6
4. – MI Bukrinsky, TL Stanwick, MP Dempsey, and M Stevenson; Quiescent T lymphocytes as an inducible virus reservoir in HIV-1 infection ; Science, 1991 ,Vol 254, Issue 5030, 423-427
5. L°Pierson T, McArthur J, Siliciano RF.Reservoirs for HIV-1: mechanisms for viral persistence in the presence of antiviral immune responses and antiretroviral therapy Annu Rev Immunol. 2000;18:665-708.
6. Gaël Petitjean, Yassine Al Tabaa, Michel Segondy and Jean Pierre Vendrell ; Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients. Retrovirology 2007, 4:60