Intra-host competition between nef–defective escape mutants and wild–type human immunodeficiency virus type 1

Abstract

Various forms of nef genes with deletions at conserved positions along the sequence have been reported to persist in human immunode¢ciency virus type 1 infected patients. We investigate the forces maintaining such variants in the proviral population. The main selection pressures are preservation of function and host immune response. The crippled Nef protein might have fewer epitopes, and as such be less visible to the speci¢c immune response, but it will lose some function. Does a trade-o¡ between avoidance of the immune response and loss of function explain the dynamics of the crippled virus found in the patients ? To answer this question, we formulated a deterministic model of the virus^host interactions. We found that when the crippled protein presents few epitopes and su¡ers little loss of function, the two viral types can coexist. Otherwise, the wild-type comes to prevail. The mutant form might initially dominate, but as the selective pressure by the CD8+ T cells decreases over the course of infection, the advantage for the crippled form of losing epitopes disappears. Hence, we go from a situation of coexistence of wild-type and mutant, to a situation of only full-length nef. The results are discussed in the context of the suggested use of live attenuated vaccines having deletions in nef.

Evasion of cytotoxic T lymphocytes is a functional constraint maintaining HIV-1 Nef expression

“…In this example, it would seem that the excess of added Nefspecific CTL overwhelmed the balance that usually favors maintenance of Nef, such that the selective advantage of losing Nef (which served as a target for the expanded CTL) outweighed the functional benefit of keeping Nef. This scenario and the data in the present study are consistent with a proposed mathematical model evaluating the pressures on Nef in vivo [32].…”

Simultaneous assessment of CD4 and MHC-I downregulation by Nef primary isolates in the context of infection

“…Additionally, it has been shown that some chronically infected individuals harbor two functionally distinct populations with respect to MHC-I downregulation (Lewis et al, 2008). Indeed there may be an evolution or trade off between different functions over time and in different in vivo contexts (Altes and Jansen, 2000). For example, Nef may optimize different functions in different tissue compartments or in response to differing immune pressure (Ali et al, 2005; Salemi et al, 2005).…”

Modelling the HIV persistence through the network of lymphocyte recirculation in vivo

“…Insights into HIV dynamics in vivo have been obtained from mathematical modelling (see e.g., ( Nowak and May, 2001 , Perelson and Nelson, 1999 )). Competition models have been formulated in the context of the dynamics of virus-host interactions in the past two decades ( Frost and McLean, 1994 , Korthals Altes and .Jansen, 2000 , McLean and Nowak, 1992 , Rong et al., 2007 , Smith and Wahl, 2004 , Smith and Wahl, 2005 , Wahl and Nowak, 2000 ). These models embedded the knowledge on the possible dynamics of HIV-1 infection into relatively complex systems of non-linear differential equations.…”