SNF Ambizione

Acute and chronic dynamics of HIV and HCV infections, within-host evolution and epidemiological outcomes

Ambizione grant (#136737) from the Swiss National Science Foundation (SNSF)

Start/End: 01.10.2011 – 30.11.2014
Approved amount: 439’722 CHF (~ 450k USD)
Applicant(s): Christian L. Althaus

Relationship between set-point HIV RNA and the production rate of target cells (from ref. 2).

Relationship between set-point HIV RNA and the production rate of target cells (from ref. 3).

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) are potentially fatal chronic virus infections of public health importance. Whereas HCV can be cleared spontaneously in some infected individuals, HIV persists in the host but some patients can maintain long-term control of HIV replication during the chronic phase. The cellular immune response, and in particular the CD8+ T cell response, has been strongly associated to play a role in determining the outcome of both HIV and HCV infections. Nevertheless, there is conflicting evidence on the importance of CD8+ T cells in viral clearance or control and it remains unclear when, how and to what extent the CD8+ T cells interfere with viral replication. Mathematical modeling plays an important role in analyzing and interpreting clinical data of patients infected with HIV or HCV. The first part of this project deals with the analysis of four different data sets that cover particular aspects of HIV and HCV infection during the acute and chronic phase. By studying the viral turnover in different patients that are infected with HIV, and the occurrence of immune escape variants in HCV, the analyses will provide novel and fundamental insights into the viral dynamics and evolution within a host. In the second part, the insights from the data analysis will be used to develop new mathematical models of virus dynamics. This will help to conceptually study the factors that can influence the differential outcomes of HIV and HCV infections and test different hypotheses about the role of CD8+ T cells on the virus dynamics. The third part of the project deals with the evolution and spread of HIV variants that confer escape from CD8+ T cell recognition. Mathematical and computational models will be developed to study the rate at which such escape variants can spread at the population level, thereby anticipating the ongoing HIV epidemic. In summary, this project will provide new insights into how CD8+ T cells shape the viral dynamics and evolution, shedding more light on the controversial issue of the role of CD8+ T cells in suppressing viral replication. Ultimately, the newly gained insights into the role of CD8+ T cells to induce a selection pressure on the virus population, both within a host and at the population level, will be important for ongoing efforts in T-cell-based vaccine design for HIV and HCV.

Major findings

The results of the sub-study of Aim 1 (Acute HIV infection) provide novel quantitative insights into the turnover and development of different subclasses of HIV-1-infected cells. The model predicts that the pool of latently infected cells becomes rapidly established during the first months of acute infection and continues to increase slowly during the first years of chronic infection (1). Having a detailed understanding of this process will be useful for the evaluation of viral eradication strategies that aim to eliminate the latent reservoir of HIV-1.

The results of the study of Aim 2 (Modeling the virus dynamics of HIV and HCV within a host) shed light on the impact of the immune response on the outcome of HIV and HCV infections. I found the death rate of infected cells to be the primary determinant for spontaneous clearance of HCV, suggesting that cytolytic immune responses play a major role in this process (2). In contrast, I showed that non-cytolytic immune responses that modulate viral production are likely to play the primary role in determining the set-point viral load levels of HIV and HCV.

Publications
  1. Althaus CL, Joos B, Perelson AS, Günthard HF. (2014) Quantifying the turnover of transcriptional subclasses of HIV-1-infected cells. PLOS Comput Biol, 10.
  2. Althaus CL. (2015) Of mice, macaques and men: scaling of virus dynamics and immune responses. Front Microbiol, 6.
  3. Althaus CL. Determinants of viral persistence and clearance during HIV and HCV infections. in preparation.