IV-drug abuse is a prominent risk factor in AIDS. Credible support can be found that opiates have no effect on AIDS progression, or are exacerbatory, or inhibitory. In a pilot monkey study, we found that AIDS progression was slowed by morphine dependency. We have subsequently initiated a large. (20 rhesus/group, morphine vs saline) study to confirm this observation. This competitive renewal application is directed at continuing this effort. Monkeys have been on opiates and virus for 1-1/2 yr. AIDS progression rate with our model cannot be judged until 3-4 yr post-virus infection. So, it is too soon to know whether opiate dependency is altering AIDS progression in this study. To date, only 2 control monkeys have died from AIDS. Mean viral titers do not differ between groups, which suggests that their progression rates will be similar; yet, monkeys on opiates show viral-immune interactions interpretable as being protective. Thus, we plan to continue this study until an endpoint in rates of progression is reached where differences between test and control animals, if they exist, will be obvious (predicted in yr-2 of the proposed grant). Viral titers and mutation rates, and potentially contributing factors like the ability of the host to repair DNA damage are all being followed in conjunction with a variety of relevant immune measures. These analyses are expected to yield important interdependent correlates of AIDS progression that will help qualify the progression outcome. An overlying second hypothesis is also being explored, i.e., that a well-maintained opiate-dependency will retard progression of neuro-AIDS. Neuropathology has been reported as elevated in heroin addicts, making this a particularly relevant current issue. We will continue examining CSF from our monkeys for this purpose to see if opiates alter viral and immune status in this compartment, and whether blood brain barrier integrity is affected. Preliminary data suggest that opiates do alter inflammation in the CSF. Also, biopsied lymph-node tissues are being examined for noradrenergic nerve integrity simultaneous with viral and immune measures. A variety of postmortem tests are planned, too, to assess somatic and neural pathology in terms of morphology, viral detection, cytokine profiles, and inflammation to look for quantitative and qualitative differences in animals exposed to morphine versus saline. This effort is being extended by a subcontract to Dr. Linda Chang to use MR Spectroscopy to test neural tissues for cell loss. Finally, many of the aforementioned types of tests, along with neuroendocrine tests, are to be used before monkeys are sacrificed in yr-4, to see whether opiate-withdrawal exacerbates virus production. These studies will test a counterhypothesis to our 'protective' hypothesis. That is, does the stress of opiate withdrawal exacerbate AIDS by inducing AIDS virus production? In the end, we expect these studies to improve knowledge about whether and how opiates modify the progression of AIDS.
