Modeling Human Immunodeficiency Virus Transmission and Infection

HIV-1 is a global pandemic with about 39 million people infected. In India, 2.9 million people are infected and about 2 lakh new infections have been reported last year. To date, there is no cure for HIV/AIDS. Current treatment, which is associated with serious side effects, only delays the onset of AIDS and death. Thus, HIV/AIDS is responsible for a global health concern imposing significant healthcare costs, especially in low- and middle-income regions such as India and Africa, and a marked loss of quality of life to infected individuals. Understanding factors impacting vaccine design and drug development via mathematical modelling of HIV-1 transmission, evolution and pathogenesis and discerning the subtype and region specific differences are a crucial part of the overall strategy of reducing the burden of HIV/AIDS. The strain dominant in India is HIV-1 subtype C (HIV-1C). Treatment guidelines have largely been based on studies on HIV-1 subtype B (HIV-1B), dominant in the west. In this thesis, we have attempted to understand the dynamics of the spread of HIV-1C, leading to new guidelines and intervention strategies applicable to India. We have for the first time estimated the basic reproductive ratio, R0, of HIV-1 subtype C (HIV-1C), a proxy for its fitness and virulence, using clinical data of infected patients from India. We employed measurements of viral load decay dynamics during treatment and estimated R0, and the critical efficacy, ec, for successful treatment of HIV-1C infection. Clinical data showed that the viral load in patients in India was significantly higher than in the west. Yet, in 6 months following the start of treatment, 87.5% had undetectable viral load, indicating an excellent response to ART, comparable to the west. We analyzed the clinical data using a mathematical model and estimated the median R0 to be 5.3. The corresponding ec was ∼0.8. These estimates of R0 and ec are smaller than current estimates for HIV-1B, suggesting that HIV-1C exhibits lower in vivo fitness compared to HIV-1B, which allows successful treatment despite high baseline viral loads. New treatment guidelines thus emerge that are less stringent than in the west. HIV-1C is far more prevalent globally than HIV-1B. This is surprising in light of our findings above of a lower fitness of HIV-1C than HIV-1B. To understand this observation, we next developed a mechanistic paradigm of HIV-1 transmission. HIV-1 has been hypothesized to optimize its transmission potential (TP) in an infected population by modulating its steady state viral load (VSS), a robust marker of virulence. The mechanism of this optimization is paradoxical and poorly understood given that HIV-1 mutates rapidly in vivo in response to selection pressure by the host immune system. We hypothesize that the HIV-1 TP is not solely a function of VSS as proposed earlier, but a function of two variables - VSS and R0, which function such that R0 is optimized within an infected individual in response to the immune system while VSS is optimized across individuals such…