Roger J Pomerantz; David L Horn


Nat Med. 2003;9(7) 

In This Article

Beyond 2003: Challenges in Translating Progress to the Developing World; Early Vaccine Attempts; Explosive Growth of Medical Knowledge; Future Agents

A recent editorial by Farmer in the New England Journal of Medicine stated, "Excellence without equity looms as a chief human-rights dilemma of health care in the twenty-first century".[69] For HIV-1 and AIDS, the great health-care challenge will be the translation and dissemination of therapeutic advances in the developed world to the millions of people living with and dying from HIV-1 infection in the developing world. This is a monumental economic challenge, as the annual direct expenditures for the care of HIV-1 in the US exceed $20,000 per patient.[70,71] Even though HIV-1 therapy may be considered cost effective in the developed world, paying for such therapy may represent an insurmountable barrier to any comprehensive therapy in the developing world. Another obstacle commonly encountered in the developing world is the lack of medical expertise and infrastructure required to administer the various complex regimens of HAART, all of which are fraught with complex medical decisions regarding resistance and drug toxicities.

In addition to the difficulty of bringing available therapies to the developing world, there are challenges to developing improved therapies and eradicating HIV infection in patients. Currently there are two approaches for increasing HIV-1-specific immunity: strategic treatment interruptions and therapeutic vaccination. Thus far, the results of structured treatment interruptions have been disappointing.[72,73] Therapeutic vaccination entails the delivery of HIV-1 components for recognition by the immune system, leading to an enhanced immune response to HIV-1 by the host.[74,75] It is known that strong immune responses, such as CD4+ T-cell proliferative responses to HIV-1 antigens and CD8+ cytotoxic T-cell responses, correlate with control of HIV-1 in long-term nonprogressors.[76,77] Current clinical studies measuring the immune response to HIV-1 antigens and epitopes may lead to knowledge applicable to effective therapeutic vaccination strategies for HIV-1-infected individuals, as well as a prophylactic vaccine.

Impeding any of the steps in the HIV-1 replication cycle might be an avenue for success in defeating the virus (Fig. 1). Simply stated, HIV-1 consists of 15 proteins and 9.7 kb of RNA.[79] One promising area of interest is to target the virally encoded enzyme integrase, which catalyzes the insertion of reverse-transcribed HIV-1 DNA into the host chromosomal DNA.[79] Another approach is to block the entry of HIV-1 through chemokine coreceptors. HIV-1 binds to both CD4+ and chemokine receptors (CXCR4 and CCR5) to gain entry into the host cell. Small molecules to inhibit HIV-1 attachment to these chemokine receptors have been produced and are able to inhibit HIV-1 replication in vitro.[80,81]

Clinical trials are now under way to document the extent of clinical activity for both integrase inhibitors and chemokine receptor entry inhibitors.[68,82]

We now need to explore the value of inhibiting HIV-1 regulatory and accessory genes, and their products. Additional targets might also be identified as important and amenable to inhibition as we learn more about the basic biology of HIV-1 disease. One example could be the Vif protein, which is important for the production of highly infectious mature virions.[78,83] Production of HIV-1 virions lacking Vif is severely restricted at a postentry, preintegration step of infection, based on an antiviral cellular factor called CEM,[15] which inhibits viral replication.[84,85] A two-amino-acid insertion mutation in Vif that disrupts activity is reported to have led to clinical, long-term nonprogression in a mother and daughter infected with HIV-1 and may indicate the importance of Vif as a target.[86]

Another factor that has made HIV-1 disease into a treatable infection is the explosion and dissemination of medical information. A MEDLINE search carried out in April 2003 found over 186,000 articles (using AIDS or HIV as search terms). In addition, basic drug discovery processes have greatly improved and may produce more lead compounds for investigation in the clinic, based now on rational drug design.