The human immunodeficiency virus: Basic concepts of infection and host response

HIV has been with us for the last decade and is likely to remain with us for the foreseeable future. Key to the pathogenesis of this virus is its ability to strike at the very heart of the immune system, thereby rendering subsequent immunologic responses limited and inadequate. Because there are unique steps in the viral life cycle that involve virus-specific proteins, it is conceivable that antiretroviral agents can be developed, which minimally affect host cellular functions while profoundly interfering with the viral life cycle. For the moment, much of the current direction of treatment research is aimed at optimizing the use of existing antiretroviral agents. This optimization necessarily involves the testing of combinations of agents used concurrently and consecutively. The results of the zidovudine/ddC combination study have been encouraging and in part have led to the development of a large four-arm, ACTG multicenter trial comparing zidovudine alone versus ddI alone versus zidovudine in combination with ddI or ddC for the treatment of HIV-infected patients with CD4 counts between 200 and 500 cells/mm³. It is of course hoped that combination therapy will result in greater and more durable responses. Prospects for an HIV-1 vaccine have improved over the last few years as more has been learned about the molecular mechanisms of the immune response to the virus. Yet even if an effective vaccine were soon to become available, proving its effectiveness would present formidable ethical and logistical challenges. For instance, the vaccine would have to be a subunit vaccine rather than a killed or inactivated virus preparation owing to the fears of infectivity of the vaccine. What populations would be targeted for vaccination in clinical trials? For any population, study participants would surely need to be counseled on ways to prevent becoming infected. In that case, an expected low infection rate would translate into few clinical end points, thereby necessitating a large and expensive trial of long duration. Yet only when sufficient numbers of end points are reached would it be known whether or not the vaccine is effective. These are only a few of the many challenges that lie ahead in HIV therapy and vaccine development.