Why and where an HIV cure is needed and how it might be achieved

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Abstract

Despite considerable global investment, only 60% of people who live with HIV currently receive antiretroviral therapy. The sustainability of current programmes remains unknown and key incidence rates are declining only modestly. Given the complexities and expenses associated with lifelong medication, developing an effective curative intervention is now a global priority. Here we review why and where a cure is needed, and how it might be achieved. We argue for expanding these efforts from resource-rich regions to sub-Saharan Africa and elsewhere: for any intervention to have an effect, region-specific biological, therapeutic and implementation issues must be addressed.

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Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation.

Liang Shan, Kai Deng, Neeta S. Shroff … (2012)

Highly active antiretroviral therapy (HAART) suppresses HIV-1 replication but cannot eliminate the virus because HIV-1 establishes latent infection. Interruption of HAART leads to a rapid rebound of viremia, so life-long treatment is required. Efforts to purge the latent reservoir have focused on reactivating latent proviruses without inducing global T cell activation. However, the killing of the infected cells after virus reactivation, which is essential for elimination of the reservoir, has not been assessed. Here we show that after reversal of latency in an in vitro model, infected resting CD4(+) T cells survived despite viral cytopathic effects, even in the presence of autologous cytolytic T lymphocytes (CTLs) from most patients on HAART. Antigen-specific stimulation of patient CTLs led to efficient killing of infected cells. These results demonstrate that stimulating HIV-1-specific CTLs prior to reactivating latent HIV-1 may be essential for successful eradication efforts and should be considered in future clinical trials. Copyright Â© 2012 Elsevier Inc. All rights reserved.

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A novel quantitative approach for measuring the reservoir of latent HIV-1 proviruses

Katherine M. Bruner, Zheng Wang, Francesco R. Simonetti … (2019)

A stable latent reservoir for HIV-1 in resting CD4+ T-cells precludes cure 1–3 . Curative strategies targeting the reservoir are being tested 4,5 and require accurate, scalable reservoir assays. The reservoir was defined with quantitative viral outgrowth assays (QVOAs) for cells releasing infectious virus following one round of T-cell activation 1 . However, QVOAs and newer assays for cells producing viral RNA after activation 6 may underestimate reservoir size because one round of activation does not induce all proviruses 7 . Many studies rely on simple PCR-based assays to detect proviral DNA regardless of transcriptional status, but the clinical relevance of these assays is unclear, as the vast majority proviruses are defective 7–9 . We describe a novel approach that separately quantifies intact and defective proviruses and show that the dynamics of cells carrying intact and defective proviruses are different in vitro and in vivo, a finding with implications for targeting the intact proviruses that are a barrier to cure.