Human Immunodeficiency Virus

Human immunodeficiency virus (HIV) is one of the greatest worldwide public health challenges of the last century. Since being identified over 20 years ago, HIV has claimed an estimated 25 million lives. Currently, an estimated 33 million individuals are living with HIV/AIDS. Although it causes infections worldwide, this virus has especially targeted areas of the developing world, with prevalence rates nearing 50% among women of child-bearing age in some areas of sub-Saharan Africa. Primary infection may be characterized by an acute viral syndrome or may be entirely asymptomatic, and individuals are often unaware of their infection. Symptomatic illness usually occurs several years after infection, and is manifested by significant-to-severe immune suppression. Although antiretroviral therapy (ART) is generally effective at suppressing viral replication, treatment is not universally available and is often associated with serious side effects. Also, due to the high rate of mutation during viral replication, ART may become ineffective in noncompliant individuals. The structure, genetics, and replication characteristics of HIV make it a challenging pathogen. HIV is a remarkably diverse virus, with two major types, and multiple subtypes and recombinant forms circulating worldwide. The viral envelope varies considerably from isolate to isolate, and has few conserved regions that can be effectively targeted by host antibody responses. Glycosylation of protein structures on the envelope coating hinder access by neutralizing antibodies, and widespread mutational change within the genome permits escape from cellular immune mechanisms. HIV preferentially infects activated host immune cells, which are diverted from their normal cellular biosynthetic pathways to produce virus particles, and undergo premature apoptosis. However, infected CD41 T cells may also remain transcriptionally silent, leaving the incorporated proviral HIV genome dormant for many years. This results in a reservoir of infected cells that persists despite apparently effective therapy.The development of an HIV vaccine that is protective and easily and economically deliverable is a daunting endeavor for scientists, public health officials, and government agencies. The field of HIV vaccine development has met with a number of recent disappointments. Both the VAXGEN antibody-based vaccine and the Merck adenovirus T-cell-stimulating vaccine showed no efficacy in protecting from infection or reducing viral loads. In fact, the Merck product, tested in the Americas and South Africa, may have led to an increased susceptibility to HIV infection in individuals with evidence of preexisting serological immunity to the adenovirus vector.A new paradigm of HIV vaccine effectiveness may need to be considered. This paradigm includes vaccines that may: (1) prevent infection; (2) allow infection that is subsequently cleared without clinical disease; (3) delay clinical progression in the vaccinated individual; or (4) minimally impact disease in the infected individual, but reduce infection of others. Several new approaches are actively being tested in HIV vaccine development. DNA and peptide-based vaccines, heterologous prime-boost regimens, and alternative viral vector are under consideration and development. Scientists continue to use many different methodologies to optimize immunogenic HIV insert sequences in order to overcome the tremendous variability presented by potential infecting viruses. Other approaches seek to increase the recognition of viral antigens through the use of adjuvants and optimized modes of immunogen delivery. The next decade will provide opportunities for these hurdles to be overcome, and will likely see the emergence of new challenges as second- and third-generation vaccines are developed. Multidisciplinary approaches to vaccination may ultimately lead to complete control of this pandemic.