Since the beginning of the epidemic in the early 1980s, the natural history of HIV infection has evolved from one of certain death to a treatable chronic condition. Currently, there are about 35 million people living with HIV and the disease was responsible for 1.5 million deaths in 2013. In the USA there are approximately 1.2 million living with HIV of which 14 % are unaware of their diagnosis. Roughly 50,000 people develop new infections annually in the USA alone.

The two agents that cause AIDS are human immunodeficiency 1 (HIV-1) and HIV-2 . These viruses are Lentiviruses that belong to the family Retroviridae. These are enveloped RNA virus es that cause slowly progressive infections which produce clinical disease after a prolonged latency. In untreated patients the subacute phase preceding clinical disease averages around 10 years. These viruses depend on, and possess, the enzyme reverse transcriptase which transforms viral RNA into proviral DNA. HIV targets CD4 cells, a central component of the immune system, and enters them by interacting with the surface coreceptors CCR5 and CXCR4. Infection leads to a steady decline of CD4 cells eventually leading to the development of AIDS in those untreated.

Current antiretroviral medications are very effective at bringing HIV under control and can result in a near-normal life-span. While public health measures have significantly decreased the incidence of new infections, it is clear that a vaccine would be the only effective way of controlling the epidemic. There have been many obstacles to the development of an effective HIV vaccine . Chief among these is the fact that there is no documented case of a human spontaneously clearing the virus. Other important factors include the antigenic diversity and hypervariability of the virus, its ability to rapidly generate escape mutants, and the lack of an ideal animal model .

Over the last 30 years, only four vaccine concepts have been evaluated in clinical efficacy trials. These include the use of purified HIV-1 envelope proteins, recombinant adenovirus and poxvirus vectors, and plasmid DNA vaccines. While there have been several phase I and phase II trials evaluating safety and immunogenicity of proposed HIV vaccine s, to date, there have only been a handful of Phase III trials that have evaluated the efficacy of HIV vaccines. Of those, only one showed a statistically significant result. Known as the “Thai trial,” RV144 was a randomized placebo-controlled trial looking at the use of a Canarypox vector vaccine expressing gp120 clad E GAG and protease from clade B boosted by AIDSVAX (rGP protein 120 from 2 clade B). Looking at a population of around 16,000 low-risk individuals, in the modified intention to-treat analysis, this vaccination strategy demonstrated a 31 % reduction in disease acquisition [ 1 ]. While the results are modest, it serves as a proof of concept that producing an effective vaccine against HIV is in fact possible.

An exciting fi eld of study in which much of the current study for HIV vaccine is focused is the concept of broadly neutralizing antibodies. These are antibodies that target the conserved regions of HIV-1 Env. Although a subset of patients develop broadly neutralizing antibodies after years of infection, only a small percentage produce antibodies that are potent as well as broad. No vaccine to date has been able to elicit a broadly neutralizing antibody response. The use of passive immunization using broadly neutralizing anti bodies remains an attractive but challenging proposal [ 2 ].

The landscape for the development of an effective HIV vaccine is one that should generate optimism amongst physicians and patients. The results of the RV-144 trial have generated follow-up studies that are currently under way [ 3 ]. This along with the advances in understanding of broadly neutralizing antibodies should be viewed as a great stride in the search for an effective vaccine.

References
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[1] Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J et al (2009) Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 361:2209–2220

[2] Chuna T-W, Murraya D, Justementa JS et al (2014) Broadly neutralizing antibodies sup press HIV in the persistent viral reservoir. Proc Natl Acad Sci U S A 111:13151–13156

[3] Barouch MD (2013) The quest for an HIV-1 vaccine-moving forward. N Engl J Med 369:2073–2076

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