Research in HIV/AIDS is a multifaceted field that includes both social and scientific efforts along with the passive influences like political will, policies and their implementation and the interest of public and private funders.  Covering all aspects of such a topic is beyond the scope of a single review. However, this review tried to bring out a trend with respect to the high sounding topics in the field. The problem faced by researchers while working with HIV have made them to think out of box and facilitated a new school of thought. The trends coming up now are the examples of this thought process. 

Keywords: HIV/AIDS

HIV/AIDS is a medical problem that has been identified, recognized and disturbed almost all globally within a few decades of its first report. The infection is primarily transmitted through a very vital life process-sex and a vital fluid for life-blood. Hence it was not just a medical condition for which treatment was uncertain and cure was not even thought about, but a bigger social problem always associated with stigma. Therefore, it was both a struggle and a challenge for medical and social fraternity to deal with infected and affected populations. As nothing was known about this problem earlier and it became an epidemic within a very short time interval sparing no corner of the globe, no immediate solution could be provided to those who were infected. With the efforts of global health agencies and determination of local governments a few resources were gathered for detection of the infection and providing the costly medicines. Scientific endeavors and social support ensured their best possible to fight with the initial panic and gradually newer and better diagnostic and treatment options were discovered and made available. However the struggle is continued till date as we have not yet seen a cure for this ailment. With this, it becomes necessary to review our progress with respect to the set timeframes and plan strategies for tomorrow by understanding the scenario of present. This review is an effort to understand the status of research in the field of HIV/AIDS, to update about recent trend and future aspirations.

2. AIDS and need for research

As stated earlier, we need to have a systematic approach balancing our scientific and social efforts in the fight with HIV/AIDS. Knowledge about the status in terms of prevalence and incidence of HIV/AIDS come from epidemiological investigations whereas new tools for understanding the virus, diagnose the infection and to fight the infection come from laboratory research. Being a multifaceted disease, AIDS need research in different areas of work. We need to device newer tools to fight infection and at the same time a big part of research goes into the implementation and assessment of the effectiveness of these tools. Not only this, but much more on social and federal fronts was required to be done and being done. A research to assess and understand societal needs in bringing infected individuals under the umbrella of treatment and care remain a crucial part of the research in AIDS.

3. Dimensions to be covered by research for a multifaceted disease-HIV/AIDS

Research on HIV/AIDS encompasses all medical research that attempts to prevent, treat, or cure HIV/AIDS, as well as research about the nature of HIV as an infectious agent and AIDS as the disease caused by HIV. Another very important aspect of the research in AIDS field is socio-behavioral research that has contributed to awareness and prevention in a big way. Understanding the societal needs is as important as understanding the viral life cycle for holistically approaching the set goals. Some areas of research worth mentioning here are:

Understanding transmission dynamics of the virus and host.
Characterization of virus with respect to its life-cycle and impact of drug and host immune pressure on the virus.
Clinical Management of HIV/AIDS
Understanding the high risk activities and designing behavioral interventions for prevention of transmission.
Designing, development and trials for newer and better preventive devices for high risk populations.
Identification and designing special interventions for high risk populations.
Associated infections and other health implications due to HIV-1 infection
Development of HIV vaccine
Exploration of newer and safer drugs which can be used to treat normal as well as drug resistant viruses.
Development of microbicides for sexually transmitted diseases
Finally to devise the clinical and management strategies for cure of HIV/AIDS
A significant progress has been made in all the areas discussed above since the first report of HIV infection. However research is ongoing for better tools. A few updates are discussed here.

4. The updates:

4.1 Prevention Research:

HIV prevention saves lives and money. As per CDC, for every HIV infection that is prevented in USA, an estimated $355,000 is saved in the cost of providing lifetime HIV treatment [1]. Prevention research can arbitrarily be classified in two

Classes-one being social and behavioral intervention to prevent new infections by educating the infected individuals as well as those who are at risk of infection. The other class of research is biomedical HIV prevention research for drugs or vaccine. AIDS Vaccine, Microbicides and ARV-based Prevention research comes under the later. Social and behavioral research is very important as every strategy that can be utilized for preventing the acquisition of transmission of HIV has one or other behavioral component associated with it. For instance, promotion of condom usage, use and acceptability of microbicides etc. require a deep understanding of social and behavioral orientation of the targeted populations. Recent research has shown that HIV risk behaviors can be reduced in any targeted population through interventions that provide risk reduction counseling, stress management and problem solving approaches. Data from Voluntary counseling and testing center’s (VCTC) have shown encouraging results on global scale. However strategies and implementation needs to be done considering the regional, environmental, ethnic and religious practices and beliefs. An example of this is male circumcision. There is compelling evidence that male circumcision reduces the risk of heterosexually acquired HIV infection in men by approximately 60% [2] Although male circumcision is normal practice in many communities, many cultures have no tradition of male circumcision, and some are strongly opposed to it. As as a result, acceptance varies greatly across the world. Encouraged by the results of a few more trials, a few countries in Eastern and Southern Africa have accepted and implemented this as a policy with a target of 80% circumcision by 2016 [3]. However, implementation need to understand that circumcision is proven to be a partial protection and behavioral components must be taken care.

Under biomedical HIV prevention research strategies vaccines, topical microbicides, such as gels, creams and foams, that can be applied to the vagina or rectum prior to sexual intercourse, and providing antiretroviral to people who are not infected with HIV but who are at high risk of acquiring HIV infection (called pre-exposure prophylaxis [PrEP]) etc. are included. Looking to the importance of these strategies, a conference was organized under ‘HIV Research for Prevention. HIV R4P’ from 28–31 October, 2014, at Cape Town, South Africa and proceedings were compiled in a special supplement of ARHR (ARHR. October 2014, 30(S1)). HIVR4P 2014 presented the latest research on Pre-exposure prophylaxis (PrEP), treatment as prevention and other biomedical HIV prevention approaches.

1.   PrEP: is a powerful HIV prevention tool and can be combined with condoms and other prevention methods to provide even greater protection than when used alone. There have been a few trials for the use of PrEP [4-7]. All participants in these trials received pills containing either PrEP or placebo (a pill without any medicine in it), along with intensive counseling on safe-sex behavior, regular testing for STDs, and a regular supply of condoms. Based on strong evidence from these clinical trials of PrEP use in high-risk populations, a few guidelines were set for PrEP use. The key remain adherence as in all of these studies, HIV transmission risk was lowest for participants who took the pill consistently.

2.  Treatment as Prevention: approach is similar to PrEP except that this is meant for those who are already infected. Treatment here is not meant to solve the global HIV epidemic, but remain important as providing treatment to people living with HIV infection to improve their health must always be the first priority. There are many other important benefits associated with this. Results of a recently concluded study showed 96% Reduction in HIV Transmission with Early ART [8,9].This study was done to see whether the early initiation of ART can prevent the sexual transmission of HIV among heterosexual couples in which one partner is HIV-infected and the other is not. This landmark study validated that early HIV treatment has a profound prevention benefit.

3.   Prevention of Mother-to-Child Transmission (MTCT): of HIV, which can occur during pregnancy, childbirth, or through breastfeeding, could prevent more than 90 percent of all cases of childhood HIV infection, especially in countries where effective antiretroviral drugs are not available. Number of research studies to develop strategies to prevent MTCT of HIV has been conducted and a few are ongoing. There have been major efforts in recent years to ensure that women get the treatment they need to keep themselves well and their children free from HIV and a number of countries are now poised to eliminate mother-to-child transmission. A recent example being Cuba that became the first country in the world to receive validation from WHO that it has eliminated mother-to-child transmission of HIV and syphilis [10].

4. Microbicides development and trials: Microbicides in context with HIV are the products that are being designed for topical (vaginal or rectal) application to reduce the user’s risk of acquiring HIV and possibly other sexually transmitted infections (STIs)1 during intercourse. In July 2010, for the first time, a microbicides was found to be both safe and effective after many failed trials with other molecules and formulations. It is a vaginal gel containing an anti-retroviral drug called tenofovir. Post-trial studies concluded that a tenofovir concentration of ≥100 ng/mL in CVF was associated with 65% protection against HIV, whereas a ≥1000 ng/mL concentration correlated with 76% protection against HIV infection [11]. Hence consistent use of gel was required for better effects.

5.   Vaccine research: When HIV was first reported in 1984, it was thought that the vaccine as like other viral infections would be ready soon. However multiple approaches, efforts and trials have been conducted till date and we still await an efficacious vaccine for HIV. Till date, four large phase III efficacy trials of HIV vaccines have been conducted in humans. The first two were of different versions of a vaccine called AIDSVAX [12]. Later we learnt that neither version prevented infection [13]. The third was the STEP trial, which closed in September 2007 - this vaccine, which had looked promising in animal studies, proved not only to have no effect in humans but actually to increase the likelihood of infection in a subset of participants. [14,15]. The RV144 trial conducted in 2009, proved to be modestly, and unexpectedly, efficacious, reducing HIV infections in recipients by 31%. This ALVAC-HIV and AIDSVAX B/E vaccine regimen was predicted to moderately reduce the risk of HIV infection in a community-based population with largely heterosexual risk [16]. Currently, no large phase III efficacy trials are being conducted. A phase IIb trial, HVTN 505, has been recently stopped as initial results showed that the vaccine was ineffective in preventing HIV infections and lowering viral load among those participants who had become infected with HIV. 

6.   Neutralizing antibody research: There are difficulties with the development of HIV-1 vaccine and in eradicating established infection; passive transfer of monoclonal antibodies is being considered for HIV-1 prevention, therapy, and cure. For the development of such antibodies individuals with long term non-progression and those who are termed as elite controllers were the main sources [17]. Different antibodies were collected and tested against a panel of viruses to find the broadly neutralizing ones. A recent study has provided enthusiastic results. This study reported the first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favorable pharmacokinetics [18]. 

4.2    Treatment research

The trial, at Rockefeller University in New York, as described under neutralizing antibody research is an option for therapeutics also as it can fight 80% of HIV strains. During the trial, eight patients who were given the highest dose of antibodies showed that the amount of HIV in their blood dropped 300-fold without any apparent side effects. However, further trials and follow-up would prove its efficacy. On the other hand, biopharmaceutical companies are focused on improved treatment regimens, more effective therapies and preventive vaccines that are either in clinical trials or awaiting review by the Food and Drug Administration (FDA). The 44 medicines and vaccines in the development pipeline include 25 antivirals, 16 vaccines and three cell/gene therapies [19]. The strategies used for their development are somehow different from the currently available options. Examples include:

· A first-in-class medicine intended to prevent HIV from breaking through the cell membrane.

· A cell therapy that modifies a patient’s own cells in an attempt to make them resistant to HIV.

·  A therapeutic vaccine designed to induce responses from T cells that play a role in immune protection against viral infections.

Some advance research has also tried to get newer and sustainable treatment options. One among these is gene therapy. In a recently published study, researchers engineered a molecule known as a chimeric antigen receptor (CAR) and inserted a gene for that molecule into blood-forming stem cells, which they transplanted into mice genetically engineered to have human immune systems. The transplant of the CAR-carrying blood stem cells gave rise to functional immune cells that could kill HIV in the mice. Consequently, the mice experienced an 80 to 95 percent drop in viral load [20].

4.3 Cure research

After a long struggle in fighting stigma and social problems associated with HIV/AIDS, the world concentrated its attention in bringing the infected ones into treatment and care systems and once that seemed to be settling down the focus is now on cure of HIV/AIDS [21]. Despite durable check on HIV replication with currently available drugs, HIV persists as latent virus in various reservoirs in our body. This reservoir which remains hidden from antiviral drugs may serve for persistence and may be reemergence of actively replicating virus in our body. Curing HIV infection will only occur if these reservoirs are identified and taken care. Global targets have been set for such research with following goals [22]:

Identify HIV reservoirs throughout the body
Determine the effects of antiretroviral therapy, chemotherapy, and other strategies on the HIV reservoir
Develop assays and model systems, including a nonhuman primate model, to quantify and study HIV latency
Characterize viral reservoirs that cause rebounding of viral levels when antiretroviral therapy is stopped
Determine the role of HIV integration on virus elimination strategies
Determine the role of HIV in hematopoietic progenitor cells regarding cure strategies
Investigate strategies that lead to purging of the latent reservoir and a cure for HIV/AIDS

A number of promising interventions which might reverse latent infection have been identified, and proof that such drugs affect HIV transcription in vivo has been provided in pilot clinical trials. One strategy to achieve HIV eradication is known as the "kick and kill" approach where a latency reversing therapy such as an HDAC inhibitor is combined with an immunotherapy to maximize the immune system's response to the latent reservoir in an effort to eliminate it. The National Institutes of Health’s (NIH) Division of AIDS and Infectious Disease Services (DAIDS) have pledged $6.6 million to support the first human clinical trial into this cure strategy. A comprehensive list of trials and studies related to the research effort to cure HIV infection going on currently has been summarized by Treatment Action Group (TAG) [23].

A recent study was published with the concept that long-term in vivo expression of a broad and potent entry inhibitor could circumvent the need for a conventional vaccine for HIV-1. The study assessed option of an adeno-associated virus (AAV) vector that continuously express broadly neutralizing antibodies [24]. They concluded that AAV delivered eCD4-Ig (a fusion ofCD4-Ig with a small CCR5-mimetic sulfopeptide) can function like an effective HIV-1 vaccine.

There have been efforts to counter HIV/AIDS with whatever means it could be. New drugs, new strategies, new approaches etc. are being welcomed, tried and funded. However, the hopes for cure are emerging with various evidences and hence the attention is more there. As a part of cure research, finding the mechanism of initial establishment of HIV infection is also crucial. Linkage of HIV initial establishment with gut tissue, micro flora and their consorted interaction with our immune systems are being explored [25]. A study on SIV infection on gut mucosal immune sensing and response to pathogens and commensal bacteria in vivo has concluded that intestinal Paneth cells are the earliest responders to viral infection and induce gut inflammation through IL-1β signaling. Reversal of the IL-1β induced gut epithelial damage by Lactobacillus plantarum suggests synergistic host-commensal interactions during early viral infection and identify these mechanisms as potential targets for therapeutic intervention [26]. Another study proposed that the gp41 antibody response in HIV infection can be derived from a pre-infection memory B cell pool triggered by gut bacteria those cross-reacts with the HIV envelope [27]. Vyboh and co-workers have further reviewed the role of gut micro biota over HIV infection and vice-versa [28]. They concluded that complex interplay between gut micro biota and altered immune system mediated by the virus contributes to disease progression and immunodeficiency and have urged for further research in this area to explore if new targets for intervention can be identified.

We have walked a long way from the date when HIV infection was first reported. It was initially thought that there would be a vaccine within a short period of time and the infection would become minor infections as like other viral diseases were. There were times when social stigma and acceptance became the biggest challenges for the management of HIV infected patients and bringing them under the umbrella of treatment and care. Also we have seen an era where is hopes of getting a vaccine or a cure were almost dead. Now, perhaps, we are not much bothered about basic requirements like diagnostics, reports etc. We are hopeful for the day that we see the cure coming in. However, there are challenges like the availability of funds for advance research, identification of hard to reach populations and providing them the treatment and preventive awareness, support of mass over and above political, cultural and religious hurdles etc. But the trend is progressive and we are hopeful. 

1. CDC (2015) CDC’s HIV Prevention Progress in the United States.

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10. WHO validates elimination of mother-to-child transmission of HIV and syphilis in Cuba.

11. Kashuba AD, Gengiah TN, Werner L, Yang KH, White NR, et al. (2015) Genital Tenofovir Concentrations Correlate With Protection Against HIV Infection in the CAPRISA 004 Trial: Importance of Adherence for Microbicide Effectiveness. J Acquir Immune Defic Syndr 69:264-269.

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17. Enrique Martin-Gayo, Maria Jose Buzon, Zhengyu Ouyang, Taylor Hickman, Jacqueline Cronin, et al. (2015) Potent CellIntrinsic Immune Responses in Dendritic Cells Facilitate HIV1Specific T Cell Immunity in HIV1 Elite Controllers. PLOS Pathogens 11: 1004930.

18. Caskey M, Klein F, Lorenzi JC, Seaman MS, West AP Jr et al. (2015) Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature 522: 487-91.

19. Phrma (2015) Learn More About Medicines in Development for HIV/AIDS.

20. Zhen A, Kamata M, Rezek V, Rick J, Levin B et al. (2015) HIV-specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells. Mol Ther.

21. Nema V (2015) now we care to cure HIV. 

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23. TAG (2015) Research to ward a Cure Trials. Available from.  

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