Summary and Perspectives

Studies of the pharmacologic control of retroviral infection have largely concentrated on HIV-1. The reason for this, of course, is the significant health problem posed by infection with this lentivirus. As with other retroviruses, HIV-1 provides numerous biochemical targets for intervention. These range from virus-receptor interaction to viral-specific enzymatic activities and regulatory mechanisms. Nevertheless, successful long-term treatment of HIV-1 infection remains an unrealized goal. Part of the difficulty lies with the inherent problems typically associated with an attempt to develop viral inhibitors that are both potent and safe. For instance, the use and dosage of many of the inhibitors of HIV-1 RT are restricted because of toxicity. However, the ability of the virus to establish a persistent infection characterized by a high viral load and high viral population turnover poses a more serious problem (Piatak et al. 1993; Saag et al. 1993; Ho et al. 1995; Wei et al. 1995; Perelson et al. 1996). This combination of characteristics permits the rapid selection of resistant viral variants which, in turn, abrogate the effectiveness of the therapy (Coffin 1995; see also Chapter 11. This view of viral dynamics in the patient has profound implications for the development of an effective therapy. It should be obvious that the problem of viral resistance is not confined to simple chemotherapy. The difficulty already experienced in developing an effective method for either prophylactic or therapeutic vaccination is a related problem; switching to a therapy based on recognition of structure or sequence of viral RNA, or for that matter any other therapeutic strategy, will have to take viral variation into account.

How can we hope to make progress in the face of such variation? The answer lies in the fact that the virus is highly adapted and that viral variants (including resistant variants) are always less fit than the wild type. An effective therapy will limit the replication of all relatively fit viral variants. In such a case, the resistant viruses will replicate less efficiently and there will be a concomitant reduction in the viral load. It should be obvious that developing therapies that can interfere with the replication of all fit variants is a daunting task and that a combination of therapeutic approaches is much more likely to be effective than is any monotherapy.

Effective management of HIV-1 infection, however, should not be our only goal. Drug therapy, although it appears to hold great promise for treating HIV-1 infections, will be of little use in the Third World, where the majority of AIDS cases exist. The kinds of HIV-1 drug therapies either available or envisioned are both too complex and too expensive for use where the need is the greatest. It should also be remembered that the treatment of an established disease is not as desirable as its prevention. Although it may be possible to slow the spread of AIDS by better education and better public health practices, there is an acute need for a simple, inexpensive, effective prophylactic vaccine.

The development of effective vaccines that can be used to block retroviral infections in animals holds out some hope. However, available data on the diversity of HIV-1 strains already extant in the human population (see Chapter 11 and the difficulties already experienced in trying to develop an effective HIV-1 vaccine suggest that the task will be extraordinarily difficult. At the moment, live attenuated vaccines would appear to be the most promising. These, however, carry with them an element of risk.

Compounding this problem is the difficulty of assessing the risk; if it takes HIV-1 approximately 10 years to cause AIDS, how long, following incubation, should one wait before declaring a live attenuated HIV-1 vaccine strain safe? Despite such questions, the need is great, and it may be that the key to success will not be so much in a direct assault on the problem, but in a deeper understanding of the biology and pathology of the AIDS virus and of the human immune system.