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

Laurelle Jackson,Gila Lustig,Sandile Cele,Richard A Neher,Khadija Khan,Andrew C Young,Jessica Hunter,Rajhmun Madansein,Alex Sigal,Yashica Ganga,Kaylesh J Dullabh,Chih-Yuan Chen,Mikael Boulle,Farina Karim,Isabella Markham Ferreira,Noel J Buckels

doi:10.7554/elife.30134

Abstract

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 transmissions of 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, then 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.

Highlights

HIV infection is known to result in extensive T cell depletion in lymph node environments (Sanchez et al, 2015), where infection is most robust (Brenchley et al, 2004; Doitsh et al, 2010; Doitsh et al, 2014; Finkel et al, 1995; Galloway et al, 2015; Mattapallil et al, 2005)
Depletion of HIV infectable target cells, in addition to onset of immune control, is thought to account for the decreased replication ratio of HIV from an initial peak in early infection (Bonhoeffer et al, 1997; Nowak and May, 2000; Perelson, 2002; Phillips, 1996; Quinones-Mateu and Arts, 2006; Ribeiro et al, 2010; Wodarz and Levy, 2007). This is consistent with observations that individuals are most infectious in the initial, acute stage of infection, where the target cell population is relatively intact and produces high viral loads (Hollingsworth et al, 2008; Wawer et al, 2005)
The optimal virulence concept in ecology proposes that virulence needs to be balanced against host survival for optimal pathogen spread (Bonhoeffer et al, 1996; Bonhoeffer and Nowak, 1994; Gandon et al, 2001; Jensen et al, 2006)

Summary

Introduction

HIV infection is known to result in extensive T cell depletion in lymph node environments (Sanchez et al, 2015), where infection is most robust (Brenchley et al, 2004; Doitsh et al, 2010; Doitsh et al, 2014; Finkel et al, 1995; Galloway et al, 2015; Mattapallil et al, 2005). Depletion of HIV infectable target cells, in addition to onset of immune control, is thought to account for the decreased replication ratio of HIV from an initial peak in early infection (Bonhoeffer et al, 1997; Nowak and May, 2000; Perelson, 2002; Phillips, 1996; Quinones-Mateu and Arts, 2006; Ribeiro et al, 2010; Wodarz and Levy, 2007).

Methods

Results

Conclusion