Biology subjects

Sigal, A.

Publications and source records attributed to Sigal, A..

3 recordsLinked to original sources

bioRxiv2018

Interference with HIV infection of the first cell is essential for viral clearance in a pre-exposure prophylaxis model

Pre-exposure prophylaxis (PrEP) uses relatively weak HIV inhibition to reduce transmission between individuals. Why this approach is successful is unclear. Here we derive and experimentally validate a mathematical model for predicting infection clearance with PrEP based on the measured effect of a drug on the HIV replication ratio and number of initial infected cells. We tested the model by inhibiting low dose HIV infection with tenofovir, which reduces infection frequency per cell, and atazanavir, which reduces the cellular burst size of viable virions. Both drugs were at concentrations which allowed similar HIV replication. Reducing infection frequency dramatically increased infection clearance, while reducing burst size did not. This indicates that initial infection is vulnerable to inhibition before it infects the first cell, but not thereafter. Our model explains why PrEP is potent at drug concentrations which are ineffective against established infection, and provides a framework to test drug effectiveness for PrEP.

bioinformatics↗

bioRxiv2017

Incomplete inhibition of HIV infection results in more HIV infected lymph node cells by reducing cell death

HIV has been reported to be cytotoxic in vitro and in lymph node infection models. Using a computational approach, we found that partial inhibition of transmission which involves multiple virions per cell could lead to increased numbers of live infected cells if the number of viral DNA copies remains above one after inhibition, as eliminating the surplus viral copies reduces cell death. Using a cell line, we observed increased numbers of live infected cells when infection was partially inhibited with the antiretroviral efavirenz or neutralizing antibody. We then used efavirenz at concentrations reported in lymph nodes to inhibit lymph node infection by partially resistant HIV mutants. We observed more live infected lymph node cells, but with fewer HIV DNA copies per cell, relative to no drug. Hence, counterintuitively, limited attenuation of HIV transmission per cell may increase live infected cell numbers in environments where the force of infection is high.

bioinformatics↗

bioRxiv2017

Viral apoptosis evasion via the MAPK pathway by use of a host long noncoding RNA

An emerging realisation of infectious disease is the high incidence of genetic instability resulting from pathogen-induced DNA lesions, often leading to classical hallmarks of cancer such as evasion of apoptosis. The Human Immunodeficiency Virus type 1 (HIV-1) induces apoptosis in CD4+ T cells but is largely non-cytopathic in macrophages, thereby leading to long-term dissemination of the pathogen specifically by these host cells. Apoptosis is triggered by double-strand breaks (DSBs), such as those induced by integrating retroviruses, and is coordinated by the p53-regulated long noncoding RNA lincRNA-p21, in a complex with its protein binding partners HuR and hnRNP-K. Here, we monitor the cellular response to infection to determine how HIV-1 induces DSBs in macrophages yet evades apoptosis in these cells. We show that the virus does so by securing the pro-survival MAP2K1/ERK2 cascade early upon entry, in a gp120-dependent manner, to orchestrate a complex dysregulation of lincRNA-p21. By sequestering HuR in the nucleus, HIV-1 enables lincRNA-p21 degradation. Simultaneously, the virus permits transcription of pro-survival genes by sequestering hnRNP-K in the cytoplasm via the MAP2K1/ERK2 pathway. Notably, this pro-survival cascade is unavailable for similar viral manipulation in CD4+ T cells. The introduction of MAP2K1, ERK2 or HDM2 inhibitors in HIV-infected macrophages results in apoptosis providing strong evidence that the viral-mediated apoptotic block can be released, specifically by restoring the nuclear interaction of lincRNA-p21 and hnRNP-K. These results reveal pathogenic control of apoptosis and DNA damage via a host long noncoding RNA, and present MAP2K1/ERK2 inhibitors as a novel therapeutic intervention strategy for HIV-1 infection in macrophages.

molecular biology↗