Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy

García, Felipe; Plana, Montserrat; Vidal, Carmen; Cruceta, Anna; O’Brien, William A.; Pantaleo, Giuseppe; Pumarola, Tomás; Gallart, Teresa; Miró, José M.; Gatell, José M.

doi:10.1097/00002030-199907300-00002

Cited by 238 publications

(123 citation statements)

References 17 publications

Supporting

Mentioning

113

Contrasting

Unclassified

Order By: Relevance

“…Second, the initiation of highly active antiretroviral therapy has been shown to lead not only to the expansion of existing memory cells (50,51), but also to the gradual restoration of both Ag-specific and anti-CD3-elicited memory T cell proliferative responses to immune stimuli (52)(53)(54) suggesting that the Ag specific memory cells are present in such patients but are "unresponsive" or "anergic." Further support for this view emanates from the finding that the interruption of highly active antiretroviral therapy in HIV-infected patients rekindles such anergy and leads to the rapid decrease of T cell responses (55). The delineation of the mechanism by which HIV down-modulates these responses would thus be an important step that would help in the design of successful reconstitution therapies.…”

Section: Discussionmentioning

confidence: 99%

Relative Resistance in the Development of T Cell Anergy in CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys

Boštík

Mayne

Villinger

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

Despite high viral loads, T cells from sooty mangabey (SM) monkeys that are naturally infected with SIV but remain clinically asymptomatic, proliferate and demonstrate normal Ag-specific memory recall CD4+ T cell responses. In contrast, CD4+ T cells from rhesus macaques (RM) experimentally infected with SIV lose Ag-specific memory recall responses and develop immunological anergy. To elucidate the mechanisms for these distinct outcomes of lentiviral infection, highly enriched alloreactive CD4+ T cells from humans, RM, and SM were anergized by TCR-only stimulation (signal 1 alone) and subsequently challenged with anti-CD3/anti-CD28 Abs (signals 1 + 2). Whereas alloreactive CD4+T cells from humans and RM became anergized, surprisingly, CD4+ T cells from SM showed marked proliferation and IL-2 synthesis after restimulation. This resistance to undergo anergy was not secondary to a global deficiency in anergy induction of CD4+ T cells from SM since incubation of CD4+ T cells with anti-CD3 alone in the presence of rapamycin readily induced anergy in these cells. The resistance to undergo anergy was reasoned to be due to the ability of CD4+ T cells from SM to synthesize IL-2 when incubated with anti-CD3 alone. Analysis of phosphorylated kinases involved in T cell activation showed that the activation of CD4+ T cells by signal 1 in SM elicited a pattern of response that required both signals 1 + 2 in humans and RM. This function of CD4+ T cells from SM may contribute to the resistance of this species to SIV-induced disease.

show abstract

Section: Discussionmentioning

confidence: 99%

Relative Resistance in the Development of T Cell Anergy in CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys

Boštík

Mayne

Villinger

et al. 2001

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…Unfortunately, with the exception of occasional anecdotal reports of sustained suppression, fairly prompt virologic relapse after discontinuation of HAART has been the predominant pattern observed thus far (13)(14)(15)(16). Given that the process of lymphocyte recovery after institution of HAART has been projected to occur on the scale of months to years, it may be necessary to continue HAART without interruption for an extended period of time before embarking on any strategy in which direct viral suppression is withdrawn (17,18).…”

mentioning

confidence: 99%

HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression

Davey

Bhat

Yoder

et al. 1999

Proc. Natl. Acad. Sci. U.S.A.

736

523

View full text Add to dashboard Cite

Identifying the immunologic and virologic consequences of discontinuing antiretroviral therapy in HIV-infected patients is of major importance in developing long-term treatment strategies for patients with HIV-1 infection. We designed a trial to characterize these parameters after interruption of highly active antiretroviral therapy (HAART) in patients who had maintained prolonged viral suppression on antiretroviral drugs. Eighteen patients with CD4 ؉ T cell counts > 350 cells͞l and viral load below the limits of detection for >1 year while on HAART were enrolled prospectively in a trial in which HAART was discontinued. Twelve of these patients had received prior IL-2 therapy and had low frequencies of resting, latently infected CD4 cells. Viral load relapse to >50 copies͞ml occurred in all 18 patients independent of prior IL-2 treatment, beginning most commonly during weeks 2-3 after cessation of HAART. The mean relapse rate constant was 0.45 (0.20 log 10 copies) day ؊1 , which was very similar to the mean viral clearance rate constant after drug resumption of 0.35 (0.15 log 10 copies) day ؊1 (P ‫؍‬ 0.28). One patient experienced a relapse delay to week 7. All patients except one experienced a relapse burden to >5,000 RNA copies͞ml. Ex vivo labeling with BrdUrd showed that CD4 and CD8 cell turnover increased after withdrawal of HAART and correlated with viral load whereas lymphocyte turnover decreased after reinitiation of drug treatment. Virologic relapse occurs rapidly in patients who discontinue suppressive drug therapy, even in patients with a markedly diminished pool of resting, latently infected CD4 ؉ T cells.HIV-1 infection ͉ antiretroviral drugs ͉ viral load ͉ relapse ͉ CD4

show abstract

“…Hence, patients require life-long therapy (1,5,(21)(22)(23)(24). The CD45RO ϩ CD4 ϩ memory T cells appear to harbor the majority of the latent virus.…”

Section: Discussionmentioning

confidence: 99%

An anti-CD45RO immunotoxin kills HIV-latently infected cells from individuals on HAART with little effect on CD8 memory

Saavedra-Lozano

Cao

Callison

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

CD4+ CD45RO+ T cells are the major latent viral reservoir in HIV-infected individuals and hence a major obstacle in curing the disease. An anti-CD45RO immunotoxin (IT) can decrease the number of both productively and latently infected CD4+ T cells obtained from HIV-infected individuals with detectable viremia. In this study, we determined whether this IT could also kill latently infected replication-competent CD4+ T cells obtained from infected individuals without detectable plasma viremia. Our results demonstrate that ex vivo treatment with the anti-CD45RO IT significantly reduced the frequency of these cells. In contrast, the IT had only a modest effect on the cytomegalalovirus-specific memory responses of CD8+ T cells. These results suggest that purging latent cells from infected individuals on highly active antiretroviral therapy with the anti-CD45RO IT might reduce the HIV latent reservoir without seriously compromising CD8+ T cell memory responses

show abstract

Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy

Cited by 238 publications

References 17 publications

Relative Resistance in the Development of T Cell Anergy in CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys

Relative Resistance in the Development of T Cell Anergy in CD4+ T Cells from Simian Immunodeficiency Virus Disease-Resistant Sooty Mangabeys

HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression

An anti-CD45RO immunotoxin kills HIV-latently infected cells from individuals on HAART with little effect on CD8 memory

Contact Info

Product

Resources

About