More than 1.2 million Americans and 37.8 million people worldwide are currently living with HIV. For these individuals, and for those who will become infected with HIV, any future vaccine will come too late, and effective antiviral therapies must be used to combat their HIV infections and HIV-associated cancers. Recently, work in the HIV Dynamics and Replication Program (HIV DRP) has been extended to include the innate immune response to viruses other than HIV, and studies of cancer viruses.
The application of therapies using combinations of antiviral drugs has shown that HIV replication in infected people can be suppressed, which provides considerable and long-lasting clinical improvement. These therapies have helped large numbers of infected individuals live relatively normal lives. Most importantly, they validate the concept that antiviral drugs can offer long-term relief to individuals with HIV infections. However, current therapies do not eliminate the virus from infected individuals; thus, lifelong treatment is required. This long-term therapy is associated with a number of challenges, including toxicity, inadequate adherence, chronic immune activation, and, in some cases, the appearance of drug-resistance mutations. Thus, there remains an urgent need to understand how HIV persists despite treatment and develops resistance to drugs; this new information can be used to develop strategies toward HIV achieving remission without antivirals and to develop long-acting drugs with reduced toxicity for the treatment of HIV infections.
The HIV DRP was formed in 1997 as the HIV Drug Resistance Program, with the mission of conducting and fostering multidisciplinary basic, translational, and clinical research focused on problems related to drug-resistant HIV. The Program has built on the existing strengths of the NCI’s basic and clinical research programs in retrovirology, drug discovery, AIDS, and AIDS malignancies, exploiting studies in structural biology, biochemistry, virology, virus-host interaction, evolution, and in vivo virus biology to better understand mechanisms of retroviral replication, persistence, and coinfections. These are areas of critical importance to the AIDS epidemic, and they raise both basic and clinical research challenges whose solution will enhance our understanding of fundamental aspects of virology and cell biology and guide the development of new effective therapeutics and therapies. Although the Program focuses primarily on HIV, drug resistance is a major concern for other infectious agents as well as cancer, and it is likely that our research will be beneficial in these and other areas. As noted earlier, the research that is being conducted in the HIV DRP has recently expanded beyond HIV to include studies of innate immunity and cancer viruses.
Because antiviral therapies for HIV are highly effective, some of the focus in the field, and within the HIV DRP, has shifted toward questions that include, but are not limited to, the interactions of HIV (and other viruses) with the host. These include basic and molecular questions involving the host cell factors that HIV exploits during its replication and factors that the host cell uses to help control the replication of HIV and other viruses. There is also an interest in how the virus is able to persist in infected individuals who have been successfully treated with antiviral drugs for many years. It now appears that some HIV-infected cells in individuals can grow and divide. This clonal expansion helps the DNA copies of the viral genome carried by the expanded cell clones to persist and contributes to the reservoir that has made developing a cure for HIV infections a challenging goal.
The scope of research conducted by HIV DRP scientists has expanded over the years to encompass a broader range of important problems in virus biology. Thus, in 2015, the name of the Program was changed to HIV Dynamics and Replication to better capture the breadth of the research carried out by the Program. In addition to basic and clinical HIV research, DRP scientists are also investigating mechanisms of virus entry into cells and evasion of cell-intrinsic immunity. These studies are being performed in the context of not only HIV but also other important human viral pathogens (e.g., Influenza A virus and SARS-CoV-2). The DRP also performs research on herpes viruses (KSHV) and papilloma viruses, specifically investigating gene expression and post-transcriptional regulation of these cancer-causing human pathogens.
