Frontiers in HIV Research

HIV has probably originated from multiple zoonotic transmissions of Simian Immunodeficiency Virus (SIV) from non-human primates to humans in West and Central Africa. There are two HIV types: HIV type 1 (HIV-1) groups M, N, O and P and HIV type 2 (HIV-2) groups A–H. Within the HIV-1 group M, nine subtypes are found, designated by the letters A–D, F–H, J, and K. Within a subtype, changes in the amino acid sequence is observed in the range of 8-17%, but it can be as high as 30%, while differences between subtypes are generally found in the range of 17-35%.

In fact, when new combinations between different HIV-1 subtypes occurs, it results in different Unique Recombinant Forms (URFs), some developed into Circulating Recombinant Forms (CRFs) as propagated in three or more epidemiologically unlinked individuals. The viruses fueling these epidemics vary according to geographical regions, with clade C virus being the most prevalent worldwide, and clade B being currently the most prevalent in the United States and Europe.

Thirty years after the first description of AIDS, an estimated 35.0 million [33.2 million–37.2 million] people were living with HIV at the end of 2013. 2.1 million [1.9–2.4 million] had become newly contaminated with HIV in 2013, including 240000 children, and 1.5 million [1.4–1.7 million] HIV-infected persons died.

The risk of HIV transmission varies widely by the type of exposure. Anal intercourse for both receptive and insertive partners has a higher risk versus vaginal intercourse, and vaginal intercourse is a higher risk act compared to oral intercourse. Also, receptive intercourse (both vaginal and anal) has an increased risk compared to insertive intercourse. Generally, the risk of HIV transmission for receptive anal intercourse, receptive vaginal intercourse and receptive oral intercourse is 0.5%, 0.1% and 0.01% per act, respectively. However, the risk varies widely depending on differences in factors such as co-occurrence with other sexually transmitted infections (STIs), level of viral load, stage of disease, and circumcision. Plasma viral load is considered as the strongest determinant of sexual transmission of HIV.

Higher rates of infection with HIV are exhibited among injection drug users mainly because of unsafe injecting behavior. The risk of HIV transmission per each drug injection is 0.67%.

Vertical transmission may occur during pregnancy by micro-transfusion of blood across the placenta; or during labor and delivery by the exposure of neonate with maternal blood and genital tract secretions, and after the birth through breastfeeding. It is estimated that 24-45% of HIV infected mothers transmit the virus to their offspring if there is no intervention. Maternal plasma viral load, co-infection with STIs, chorioamnionitis, concurrent HCV infection or active tuberculosis, and vaginal versus caesarean delivery are associated with the increased risk of vertical transmission. Contributing factors to mother to child transmission include breastfeeding pattern and duration, health status of maternal breast, and high plasma or breast milk viral load.

Mother-to-child transmission of human immunodeficiency virus type 1 (HIV) occurs during gestation, during delivery, and during breast feeding. In an unprotected mother-child pair, transmission over-all occurs in 30-40%, with about one quarter of these transmissions in utero, one half during delivery, and one quarter during breast feeding. Most in utero transmission occurs in the third trimester. There are many risk factors for transmission, but the most important are the maternal viral load and the maternal CD4 concentration. Antiretroviral treatment of the mother has a potent preventive effect but must be administered throughout the risk period (that is, from early second trimester through the end of breast feeding). For in utero and intrapartum transmission, treatment probably acts through two mechanisms, namely pre-exposure prophylaxis in the fetus or newborn, and reduction in maternal viral load. Adequate voluntary counseling and testing for HIV and access to antiretroviral drugs are now critical preventive issues in this important mode of transmission.

The Acquired Immune Deficiency Syndrome (AIDS) is one of the major causes of deaths among women of reproductive age and a significant contributor to high infant mortality rates globally. Mother-to-child transmission occurs when HIV infection is transmitted from an HIV infected mother to her baby in pregnancy, labour, delivery and breastfeeding. Preventing Mother-to-Child Transmission (PMTCT) of HIV is critical to save lives and restrain the impact of the HIV epidemic. Mother-t- -child transmission before, during and after delivery can be the result of HIV transmission in 30-35% of infants of HIV-positive infected mothers. In the past three decades, HIV screening and treatment for pregnant females as well as prophylaxis for perinatal HIV transmission prevention were developed. Because of prenatal HIV counselling and testing, antiretroviral prophylaxis, programmed caesarean sections and evading of breastfeeding, the amount of perinatal HIV transmission has significantly diminished in the world today. The World Health Organization’s protocol recommends the increase of the eligibility of pregnant females with HIV infection to lifelong antiretroviral therapy when possible in order to achieve optimum health outcomes. The main missed opportunity in preventing perinatal HIV infection is a lack of prenatal care. Antenatal HIV counselling comprising testing of pregnant females is an efficient medical intervention that contributes to PMTCT of HIV.

HIV infects cells of the immune system, particularly T CD4 helper cells. Interaction of viral proteins with the cell, modulate many signaling pathways in the immune system. This interaction facilitate to the HIV replication, trafficking and infection. The starting point in signaling pathways is the attachment of HIV envelope protein gp120 to the CD4 receptor and CCR5 or CXCR4 coreceptor. Such events result in calcium fluctuation and activation of various Protein Kinase C (PKC) isoforms. Moreover, it was reported that gp120 mediates chemotaxis and actin cytoskeleton rearrangement. After the integration of the provirus and gene expression, HIV regulatory and accessory proteins modulate the enzymatic activity of some of the protein kinases. Accessory proteins induction of G2 cell cycle arrest is found to reduce human immune functions through protection against T-cell clonal expansion that would optimize cellular environment for maximal viral replication. Also induced cell cycle arrest via a DNA damage-sensitive pathway in HIV infection has been shown. HIV infects and induces apoptosis of circulating CD4 T and CD34 multi-potent hematopoietic progenitor cells.

HIV infection is regarded as one of the most important causes of mortality disease worldwide. The pathogenesis of HIV infection is complex and a multi-factorial process that is influenced by both viral and host factors. These factors play an important role in disease progression in HIV infected people. The HIV infected individuals eventually develop AIDS in a different progressive rate. The biological correlates to progression rate toward AIDS remain to be elusive. A variety of factors including host genetic susceptibility, immune function, viral genetic variability and coinfections with several microbial agents may affect the rate of progression of infection. This chapter provides information on most important factors that regulate the rate of progression of HIV infection toward AIDS.

The human immunodeficiency virus (HIV) belongs to the lentivirus a subgroup of Retroviruses belongs to the Retroviridae family that attacks the immune system. The last stage of HIV infection is AIDS. HIV is absurdly simple, albeit surprisingly complex. The virus is composed of nine genes encoding 15 different proteins. The literature has reported a large number of protein interactions of HIV and human proteins. Accordingly, many human host factors have been described to be important for HIV infection and replication. Systems biology (also known as Systeomics) is an approach to study systematically complex interactions within biological systems, and to integrate and analyze complex data sets from multiple experimental sources. Long-term non progressors are patients who remain AIDS-free for more than 10 years. In this group there are two subgroups: 1. virologic controllers who maintain the viral load below 2,000 RNA copies/mL and 2. elite controllers who have undetectable viral load or below 50 RNA copies/mL. Systems biology study of elite controllers provides an opportunity to analyze the immune system response which is uniquely endowed with the capacity to retain a long-term control of HIV replication.

In HIV infected patients, tuberculosis is the leading cause of death through the world. According to some World Health Organization (WHO) reports, the risk of tuberculosis disease in People Living with HIV (PLHIV) is about 10-20 times greater than people without HIV. The risk of developing tuberculosis disease in PPD positive HIV infected is about 10% annually but in HIV un-infected people is about 10% throughout their life. HIV accelerates the progression of tuberculosis infection toward disease both in recent and latent infection of TB. Pulmonary tuberculosis is the most common type of TB and its symptoms are related to the immune status of the patients and the level of progression to AIDS. Usually, signs and symptoms of tuberculosis are mild and it is difficult to diagnose. In smear negative pulmonary TB which is mostly observed in advanced HIV infection, mortality and morbidity would be higher due to the delay in establishing the diagnosis. Considering that reactivation of Latent TB (LTB) to active tuberculosis is more prevalent in PLHIV compared to HIV negative people, the diagnosis of LTB infection would be an important priority and screenings for TB should be done periodically among PLHIV as a priority. Any PLHIV with suspected LTB is eligible for isoniazid (INH) prophylaxis. All PLHIV with tuberculosis disease should be under Antiretroviral Therapy (ART) irrespective of CD4 cell count.

Due to sharing common routes for transmission, a significant portion of HIV infected patients are co-infected with hepatitis related viruses. It is well documented that the prognosis, pathological pathways, immunological aspects and finally drug responsiveness are different between mono versus co-infected patients. Although the detailed mechanisms regarding disease exacerbation during HIV and hepatitis virus coinfection remain uncovered, recent findings are promising in the better understanding of the interactions that, in turn maybe valuable in drug discovery.

Close interaction of viruses at common site of replication, synergic actions of proteins, changing the immune response and remodeling the cell milieu through miRNA profile are among possible manners of cooperation/counteraction between HIV and hepatitis viruses that are taken into consideration here.

As HIV infection tends to accelerate the progression of HCV and HBV infections, clinical management of this patient group must be considered more seriously. All HIV cases should be tested for HCV and HBV serological/molecular markers for further management in clinical setting and special therapeutic trend for virus control also should be employed as well.

An HIV test detects immunoglobulins against the virus or the genetic material (DNA or RNA) of HIV in the blood or specimen. P24 antigen, as a HIV core protein, momentarily becomes visible in the bloodstream during the ramp up phase when HIV-1 RNA concentration is increased up to 10,000 copies/mL.

Current rapid diagnostic tests possess high sensitivity and specificity (> 99%) and could be practical for screening individuals as they provide results in 20 minutes or less. A positive rapid HIV test results should be verified with using a supplemental test (namely, Western blot or RNA). The Western blot (an immunoblot test) detects antibodies to viral proteins and it is performed to confirm two positive ELISA tests. This confirmatory test is the gold standard among the diagnostic tests of HIV infection. ELISA is the most common HIV test performed to assay antibodies to HIV. One of the EIA-based tests is p24 antigen. New combined fourth-generation EIA antigen-antibody tests p24 antigen and anti-HIV-1/2 antibodies simultaneously. PCR is used for finding the DNA or RNA of HIV in white blood cells. This technique has high sensitivity and specificity and detects very small number of viral particles.

Antiretroviral therapy (ART) has led to dramatical improvements in the prognosis of people living with HIV. ART suppresses viral replication, reconstitutes the immune system, decreases the possibility of many HIV-related complications, and lowers the risk of HIV acquisition. Despite of substantial health benefits of ART, it accompanies its own limits. ART does not cure HIV infection and needs taking several medicines simultaneously. It causes numerous adverse effects, it is expensive and efficacy requires complete adherence. Poor adherence leads to emergence of resistance virus and finally treatment failure.

However ART is now recommended for everyone with HIV regardless of CD4 count and stage of infection. Evidences in favor of earlier ART initiation include clinical trials, better understanding of viral dynamics, effect of inflammation on body organs, newer medications that are better tolerated, data derived from cohort studies, and public health benefits of ART in preventing HIV transmission. Concerns about early ART initiation include effect of long term ART toxicity, impact of possible ART nonadherence on viral resistance, and feasibility of implementing early ART.

Based on currently existing evidences, ART is recommended for all HIV-infected individuals. The suggestion is the strongest for people with lower counts of CD4 cells, or for those with pregnancy, history of AIDS-defining illness, any type of tuberculosis, acute opportunistic infections, HIV associated nephropathy, HBV co-infection and for all children <2 years old.

Interventions to prevent mother-to-child transmission (MTCT) of HIV have become increasingly efficacious over time. Furthermore, regimens and treatment protocols have become increasingly simplified to facilitate coverage at all levels of care and reduce time-to-initiation of prophylaxis regimens. Yet, a substantial number of HIV-infected pregnant women are still not being reached by PMTCT services globally. Although a challenging prospect, we have the tools to end the transmission of HIV from mothers to babies – now is the time for communities to redouble efforts to more effectively implement PMTCT strategies to reach this critical goal.

The ability of HIV to mutate and replicate in the presence of antiretroviral therapy (ART) drugs are called HIV drug resistance. There are many reasons for HIV drug resistance happening. Some determinants are related to virus such as infidel reverse transcriptase, error-prone replication, etc. The appearance of drug resistance mutations and viral evolution could be a result of continuing HIV-1 replication in ART among some infected subjects. A wide range of mechanisms has been described with difference characteristics for different classes of drugs and also for drugs of a given class. New antiretroviral (ARV) drugs which are often applied in treatment-experienced patients include the entry inhibitor (Enfuvirtide), protease inhibitors (PIs) (Darunavir and Tipranavir), a C-C chemokine receptor (CCR) type 5 antagonist (Maraviroc), an integrase inhibitor (Raltegravir) and a non-nucleoside reverse transcriptase inhibitor (NNRTI) (Etravirine). The overwhelming data presented in journals and at scientific meetings helps staying informed about current issues, but makes new developments a daunting task.

HIV spread in many developing countries is high as a result of homosexual, heterosexual intercourses and drug abusing. Most HIV infected individuals are attributable to heterosexual intercourse. There are several biologic and behavioral risk factors lead switching a discordant couple to concordant one such as having a high HIV viral load, living together, being uncircumcised for men, and reporting a Sexually Transmitted Disease (STD) within the six months before the beginning of consensual sex intercourse for women. Strategies on prevention includes the use of condom, abstinence and bed separation, contractual agreements for outside sexual partners, and cessation of relationships for any couple, providing early sexually transmitted disease diagnosis and treatment, antiretroviral therapy (ART), and specially designed counseling to HIV discordant couples in stable relationship. ART can protect against the HIV transmission from an infected sexual partner to an uninfected one by reducing viral replication.

The invention and administration of novel antiretroviral therapies (ART) has led to the increased lifespan of People Living with HIV (PLHIV) especially in the developed world and thus, we are facing with increased number of HIV infected people over the age of 50 years. It seems that HIV infection may accelerate the aging process by accelerating the shortening of telomeres. Several adverse habits such as smoking and drug abuse as well as co-infection with other pathogens are more common among PLHIV. So, by increasing the age, inappropriate lifestyle and adverse habits such as cigarette smoking, drinking a lot of coffee, being physically inactive or inappropriate activity, opium and drug abuse and alcoholism put people in higher risk of osteoporosis. Several issues should be considered about aging like osteoporosis, neurocognitive impairment, cardiovascular disorders, and impairment of liver function along with the especial consideration about ART in elderly. There are several recommendations for slowing down the aging process in PLHIV. The cessation of cigarette smoking is the main step to prevent undesirable complications such as lung diseases and cancer, increased risk of heart attacks and strokes, bone mineral loss, muscle wasting and memory disorders. Drug abuse, especially some newer drugs like amphetamines and “crystal” may lead to several memory and behavioral impairment, depression and suicide. Regular exercise is another health habit that should be promoted among older PLHIV.

Today we know that for new HIV infection prevention, there are some effective and feasible programs such as needle exchange, behavioral interventions and antiretroviral therapy (ART). The main component to maintaining behavioral changes is to find novel techniques and know how to stay motivated and also use combination of techniques and methods. This is what researcher and health providers call Biomedical and Behavioral interventions in prevention of HIV infection. Current evidence confirms the efficacy of behavioral interventions in lowering HIV acquisition versus standard care or no intervention. Biomedical intervention is another effective program for HIV prevention, where medical and clinical approaches are used to decrease HIV infection. As HIV infection rates are strongly influenced by human behavior, behavioral changes has long been understood as essential to curb the prevalence of infection. In all cases where a decrease in prevalence has been observed, broad-based changes in behavior were the key of success. Besides behavior change strategies, it is necessary to consider the accessibility to novel biomedical HIV prevention modalities such as vaccines and microbicides. The combination of behavioral changes and application of medical treatment (as ARV or Drug treatment such as Methadone and preventive treatments like microbicides) is regarded as the best effective intervention aganist HIV acquisition.

The Human Immunodeficiency Virus and AIDS (HIV/AIDS) pandemic remains a public health challenge and a significant obstacle to socioeconomic development especially in developing countries. HIV/AIDS is a serious disease and has claimed millions of lives across the world in recent years. Many Individuals, families and communities including adults and children from across the world, particularly in low-and middle-income countries have been affected by this scourge. To address this problem, community involvement in HIV/AIDS prevention has been recognized, particularly because HIV/AIDS acquisition and transmission occur through community interactions and via complex social networks. Recognition of factors contributing to susceptibility and the spread of HIV/AIDS within countries, societies, communities and populations groups is necessary in order to halt this pandemic. Recognising these factors will inform the development of strategies to address the epidemic within general communities and within specific key population groups. Networks of individuals such as sexual partners, community members and societies need to be recognised as important in HIV transmission and prevention and understanding of communities dynamics including within families, friends and acquaintances should be the first entry point for HIV/AIDS management strategies. Involvement of communities will include developing and implementing community-based approaches to HIV counseling, testing, treatment and prevention. Effective linkages of these approaches with health facilitybased services and eradicating the barriers that key populations face in accessing these services are necessary measures. Improving policies and interventions including providing effective education to various key populations and subgroups will facilitate effective life-saving choices.

In order to control HIV epidemic, people should avoid high-risk behaviors related to the transmission of HIV regardless of their HIV status. The practice of best known strategies for avoiding HIV infection is both true for People Living with HIV (PLHIVs) and the sero-negative people. However, HIV may be transmitted via two scenarios: the first is that the HIV-positive person is unaware of his/her sero-status, and the second is that the HIV-positive person ignores his/her sero-positivity.

Positive Health, Dignity and Prevention (PHDP) covers a broad spectrum of policies and activities not only for PLHIVs but also for all of the members of a community, hence we all have responsibilities in the control of HIV epidemic.

Positive Health, Dignity and Prevention is not just a new name for the concept of HIV prevention for and by people living with HIV, formerly known as ‘positive prevention’. Implementation of PHDP would not be similar in different settings (i.e. available resources, stages of the epidemic, etc.); but in all communities, eight major components have been introduced as the framework of PHDP activities, that are: advocacy, building evidence, coverage scale up, increase in access to services, serodiscordant couples protection, influence the responsibilities of PLHIVs, stigma and discrimination reduction and scaling up and supporting the social capital

Aiming the positive prevention, psychosocial support and reduction of stigma and discrimination, positive clubs have been established in Iran since 2006. We created a systematic management procedure using the Logical Framework Approach (LFA) and Work Breakdown Structure (WBS). Based on this model, a central council including trained people living with HIV (PLHIV) provides the management for positive clubs. Subsequently, under the supervision of this council, different practical committees are formed. These committees are in close interaction with each other and by participation of HIV positive and negative volunteers, we may anticipate the empowerment of people living with HIV as well as reduction of stigma and discrimination at the community level. The objective of this chapter is to discuss a conceptual model based on LFA and WBS in order to identify appropriate management and increase participation and empowerment of PLHIV in positive clubs. Challenges and recommendations of implementing this type of model for prevention efforts are also discussed.

Various factors should be considered when deciding whether integration of HIV/AIDS services into Primary Health Care (PHC) would be beneficial or not. Many studies have stated the necessity of integrating HIV/AIDS programs and Sexually Transmitted Infections (STIs) in PHC and the positive impacts of this integration on a number of PHC goals; however, lack of a monitoring and evaluation (M&E) system makes it difficult to assess the efficiency of the integration into PHC. Considering the scale-up of care and treatment for HIV/AIDS in developing countries, there is increased debate that intensified attention to HIV programs may lead to declines in delivery of other PHC services.

Overall most evidences establish that integrated services can exert a positive effect on client satisfaction, leading to improved access to component services, and reduced HIV stigma, and also these are cost-effective. Key aspects of integration programs include: co-location of services, provision of effective substance use treatment, cross-training of care providers, and provision of enhanced monitoring of drug-drug interactions. Key components in implementing this agenda will be fostering the political tendency to fund infrastructure and service delivery, expanding street-level outreach services to injection drug users, and training community health workers able to cost effectively delivering these services.

HIV testing strategies should be carefully tailored to specific settings and populations. Screening algorithms typically include rapid test, ELISA and Western blot testing cascades. Over the counter consumer tests for oral fluids are expanding in developed countries, and early infant diagnosis screening programs such as Dried Blood Spot (DBS) testing are expanding in developing countries with high HIV prevalence. Advanced nucleic and PCR based testing platforms continue to be simplified as Point of Care (POC) equipment by numerous manufacturers. Psychosocial support and counseling are critical components of effective HIV testing programs in any community, and serve as a bridge between testing activities and early uptake to treatment regimens.

Monitoring and evaluation is necessary for any program management endeavor however it has been a challenge for application to HIV/AIDS projects globally because of the multidisciplinary and multidimensional aspects of the epidemic. Results-based management has been the main driver behind monitoring and evaluation efforts with various methodologies and indicators used for different stages of the results chain. Complexity of the HIV/AIDS epidemic necessitates the use of triangulation approach and complexity science related methods in studying various HIV aspects from biology to social dynamics and policy-making. Participatory methods have also been utilized for enhancing trust, ownership and empowerment within affected communities. Some frameworks are introduced to help planning and implementing national monitoring and evaluation systems. The future of monitoring and evaluation could be more promising for ensuring accountability and scientific rigor.

In many countries access to some populations most at risk of contracting HIV is limited. Thus conventional sampling methods cannot be utilized for studying various aspects of the epidemic among those populations. Respondent-Driven Sampling (RDS) and Time-Location Sampling (TLS) methods are developed during the recent years to allow having more accurate and more generalizable estimates on the characteristics of the participants. RDS uses the links in the social network of participants for recruitment of new ones and TLS uses the places where the potential participants usually gather. Both methods have assumptions and limitations which should be considered when applying them to different groups and situations. Prior formative research may provide invaluable information on some factors which may influence the researchers’ choice for using these methods including cost, time, feasibility and coverage of target population. This may also help in guiding development of public health interventions to mitigate the risks. Some statistical software is available for analysing data gathered from samples together with some modifications and tricks to decrease bias.

Despite the publication of many papers on the HIV/AIDS field, the central topics and subjects of research is not clearly determined yet. Therefore, in this chapter we aimed to present the information that may be guide researchers in the field of HIV/AIDS. In order to find the most common studied topics we searched for the related keywords in PubMed and Science-direct. This chapter presents the results of a review of all articles that were published in these databases.

Moreover, we selected the top three journals and studied their most recent issues. All articles published in these journals were classified in view of their subjects, so that to identify and determine the current important topics in the field of HIV/AIDS all over the world; additionally, we tried to list about two percent of all articles which contained HIV/AIDS as their keywords and have been published in PubMed so far. Overall, 4.2% of all articles which were published in Science-direct-indexed journals contained HIV/AIDS as keywords in their titles. The most common and important studied topics include the followings: epidemiology and social topics, cure and antiretroviral therapy, co-morbidity in HIV/AIDS, virology and serology, and HIV/AIDS and cancer.

Epidemiology of HIV/AIDS is still the most frequent topic of research. Most of the reviewed studies were carried out in this field; however, as we found HIV/AIDS treatment planning was also among the most important studied topics. In addition, according to our findings, clinical trials have been increasingly utilized as a research method in the last 10 years.