HIV-1 dynamics revisited: biphasic decay by cytotoxic T lymphocyte killing?

The biphasic decay of blood viraemia in patients being treated for human immunodeficiency virus type 1 (HIV-1) infection has been explained as the decay of two distinct populations of cells: the rapid death of productively infected cells followed by the much slower elimination of a second population the identity of which remains unknown. Here we advance an alternative explanation based on the immune response against a single population of infected cells. We show that the biphasic decay can be explained simply, without invoking multiple compartments: viral load falls quickly while cytotoxic T lymphocytes (CTL) are still abundant, and more slowly as CTL disappear. We propose a method to test this idea, and develop a framework that is readily applicable to treatment of other infections.

Fluctuations in HIV-1 viral load are correlated to CD4+ T-lymphocyte count during the natural course of infection.

Viral load fluctuates during the natural course of asymptomatic HIV-1 infection. It is often assumed that these fluctuations are random around a set point or underlying growth trend. Using longitudinal data, we tested whether fluctuations in viral load can be better explained by changes in CD4+ T-cell count than by a set point or trend of exponential growth. The correspondence between viral load and CD4+ T-cell count could be described by a simple mathematical relation. Using a bootstrapping approach, the hypothesis that viral load fluctuations are random around a set point was rejected with p < .00005. The hypothesis that viral load fluctuations are random around a trend of exponential growth was rejected with p < .005. Viral load data was explained better by changes in CD4+ T-cell counts than by a set point or by a trend of exponential growth. The implications of this finding for improved prognostication are discussed.

A new theory of cytotoxic T-lymphocyte memory: implications for HIV treatment.

We use simple mathematical models to examine the dynamics of primary and secondary cytotoxic T-lymphocyte (CTL) responses to viral infections. In particular, we are interested in conditions required to resolve the infection and to protect the host upon secondary challenge. While protection against reinfection is only effective in a restricted set of circumstances, we find that resolution of the primary infection requires persistence of CTL precursors (GTLp), as well as a fast rate of activation of the CTLp. Since these are commonly the defining characteristics of CTL memory, we propose that CTL memory may have evolved in order to clear the virus during primary challenge. We show experimental data from lymphocytic choriomeningitis virus infection in mice, supporting our theory on CTL memory. We adapt our models to HIV and find that immune impairment during the primary phase of the infection may result in the failure to establish CTL memory which in turn leads to viral persistence. Based on our models we suggest conceptual treatment regimes which ensure establishment of CTL memory. This would allow the immune response to control HIV in the long term in the absence of continued therapy.

Competitive coexistence in antiviral immunity.

Adaptive immunity to viruses in vertebrates is mediated by two distinct but complementary branches of the immune system: the cellular response, which eliminates infected cells, and the humoral response, which eliminates infectious virus. This leads to an interesting contest, since the two responses compete, albeit indirectly, for proliferative stimuli. How can a host mount a coordinated antiviral campaign? Here we show that competition may lead to a state of "competitive coexistence" in which, counterintuitively, each branch complements the other, with clinical benefit to the host. The principle is similar to free-market economics, in which firms compete, but the consumer benefits. Experimental evidence suggests this is a useful paradigm in antiviral immunity.

Transient antiretroviral treatment during acute simian immunodeficiency virus infection facilitates long-term control of the virus.

Experimental evidence and mathematical models indicate that CD4+ T-cell help is required to generate memory cytotoxicT-lymphocyte precursors (CTLp) that are capable of persisting without ongoing antigenic stimulation, and that such responses are necessary to clear an infection or to control it in the long term. Here we analyse mathematical models of simian immunodeficiency virus (SIV) replication in macaques, assuming that SIV impairs specific CD4+ T-cell responses. According to the models, fast viral replication during the initial stages of primary infection can result in failure to generate sufficient long-lived memory CTLp required to control the infection in the long term. Modelling of drug therapy during the acute phase of the infection indicates that transient treatment can minimize the amount of virus-induced immune impairment, allowing a more effective initial immune sensitization. The result is the development of high levels of memory CTLp that are capable of controlling SIV replication in the long term, in the absence of continuous treament. In the model, the success of treatment depends crucially on the timing and duration of antiretroviral therapy. Data on SIV-infected macaques receiving transient drug therapy during acute infection support these theoretical predictions. The data and modelling suggest that among subjects controlling SIV replication most efficiently after treatment, there is a positive correlation between cellular immune responses and virus load in the post-acute stage of infection. Among subjects showing less-efficient virus control, the correlation is negative. We discuss our findings in relation to previously published data on HIV infection.

A simple relationship between viral load and survival time in HIV-1 infection.

Despite important recent insights into the short-term dynamics of HIV-1 infection, our understanding of the long-term pathogenesis of AIDS remains unclear. Using an approach that places rapid progressors, typical progressors, and nonprogressors on a single clinical spectrum of disease progression, we quantitate the previously reported relationship between viral load and survival time. We introduce the concept of viral constant, present evidence that this quantity is conserved across patients, and explore the immunopathological implications of this finding. We conclude with a quantitative approach for assessing the benefits of a given regime of antiviral therapy.