Fig. 1. Psycho Killer Virologist.

In my spare time. . .

    I am an Associate Investigator at Blood Systems Research Institute and an Associate Professor of Laboratory Medicine at the University of California, San Francisco.  My research  focuses on the molecular evolution of human immunodeficiency virus type-1 (HIV-1). Check out my CV if you'd like more detailed info on my background and experience.  You can also check out a new UCSF press release on my work, a UCSF press release from a few years ago, a web profile of my research on the UC Berkeley Evolution website, or a video of an interview I gave at the California Academy of Sciences.

Fig. 2. Life cycle of HIV-1.

Fig. 3. A silly schematic depicting what I do.

    As everyone knows, HIV is the causative agent behind the AIDS epidemic. To date, there is no cure for HIV, and no effective prophylactic vaccine. Why is it that there is neither cure nor vaccine after over two decades of intense research on this subject? There are a few basic facts about the biology of HIV that have made its management a nightmare:

1) HIV has a high mutation rate (~0.0001 mutations/base/replication event - compare this to our own mutation rate which is ~0.00000000001 mutations/base/replication event). Basically, this means that when HIV is targeted by the immune system or some sort of manmade antiretroviral agent, it easily mutates into something that is no longer effectively targeted and controlled.

2) As a consequence of this high mutation rate, there is a tremendous amount of HIV genetic diversity in the world. It is incredibly difficult to design or even imagine a single vaccine that would effectively prevent infection by such a wide spectrum of variants.

3) HIV has specific mechanisms in place to avoid detection and destruction by the immune system: for instance, the virus downregulates the expression of cell surface molecules that present viral antigens to the immune system, thereby rendering the cells that they use as factories of replication invisible to the cellular immune response.

4) HIV integrates its genome into the genome of the host cell, making it the penultimate chronic pathogen. It can remain latent for long periods of time in non-dividing cells where it is essentially invisible to the immune system, then it can reawaken unpredictably at some point in the future and start replicating again. It is very, very difficult to seek out and destroy something that has no detectable activity associated with it.

5) HIV directly infects immune cells (e.g. macrophages and CD4+ T lymphocytes). The immune system reacts to infection by generating large numbers of immune cells to destroy the invading pathogen; in the case of HIV, these cells then serve as new potential sites of viral replication.
    O.K. That was already quite a lengthy soliloquy, and I haven't even mentioned a single detail about what I personally have to do with any of this. My work touches on items 1-3 in the list above. Here's what I do in a nutshell:

    HIV infects multiple tissues within the human body: lymph nodes, spleen, peripheral blood, prostate, epidydimis, vaginal mucosa, brain, cerebrospinal fluid, thymus, etc. etc. etc. Each one of these tissues can be thought of as a discrete compartment or vessel that the virus tries to make a living in. Each one of these compartments, in turn, has its own distinct immunological properties and target cell characteristics that the virus has to deal with. Since HIV mutates so readily, we should expect it to evolve different optimal strategies in each tissue to reflect these compartment-specific differences. My job is to explore how heterogeneity within the human body affects the molecular evolution of HIV-1, using a combination of experimental and computational tools.
    Although I mentioned a veritable cornucopia of tissues that serve as sites of replication for HIV, I mainly focus on three anatomic compartments: the central nervous system (e.g. brain and cerebrospinal fluid), peripheral tissues (e.g. lymph nodes and blood plasma), and genital tissues (e.g. prostate and seminal fluid). I compare and contrast strains of HIV-1 derived from these compartments by analyzing their genetic sequences and measuring aspects of their phenotype using in vitro cell culture.
    An obvious question is: why do I care? Well, there are several reasons, but I'll list a couple:

1) HIV infection of the central nervous system (CNS) leads to severe neurological disorders (e.g. dementia) in up to 50% of untreated patients. In addition, the CNS is a sanctuary site for HIV; many antiretroviral drugs do not efficiently permeate the blood-brain barrier, and the brain has relatively little immune surveillance under normal physiological conditions. In other words, even when the virus is kept at bay in peripheral tissues it may still be actively replicating in the brain. So, if we can identify a genotypic and phenotypic signature associated with CNS-derived HIV-1, we should be able to specifically target it, suppress its replication, and prevent the onset of debilitating neurological symptoms.

2) AIDS is predominantly a sexually-transmitted epidemic (though parenteral and vertical transmission routes do contribute significantly). If only select variants of HIV can replicate efficiently within genital tissues, we should focus our energies on combatting those particular variants in order to stop the spread of the epidemic. Even though the issue of worldwide diversity in HIV-1 seems insurmountable, perhaps we'll find that only a fraction of that diversity is relevant to the management of the AIDS epidemic.

Fig. 4. An example of a viral phenotype that I measure in vitro: MHC class I down-modulation.

Fig. 5. Phylogeny describing the extensive genetic diversity within the primate lentiviruses.

    When it's all said and done, hopefully I will wind up contributing at least some miniscule kernel of wisdom to the Big Picture. Wish me luck. I'll keep everyone posted. . .
Here are some related links for you to check out:
	•	My Curriculum Vitae - email me for a more printer friendly version.
	•	UCSF Center For Aids Research (where I work these days)
	•	Centers for Disease Control and Prevention HIV/AIDS info page
	•	World Health Organization HIV/AIDS info page