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Human body serves as a natural habitat for many organisms. It has been proven for ages that there is a balance in nature for everything. Like human rely on earth for resources, there are certain organisms which rely on human body to survive. These microbes are said to be in symbiotic relationship with human body (1). In the course of time, it is apparent that the definition of healthy being does not mean that a person is germ free, rather lives in symbiotic relationship with them. And moreover recent studies suggest that various viruses are also scooped into the scope of symbiotically living microbes in human body and maintain a dynamic symbiotic relationship (2). When a microbe invades the immune system and try to create favorable environment for its own existence, disturbs this dynamic relationship. And when host's system fails to restore the dynamics of this relationship, the invading microbe becomes a pathogen. Although the hosts of these microbes have developed immunity to defend themselves since the evolutionary era, the microbes also developed strategies to counter and evade host immune responses as well as exploit and modulate cell surface receptors and productive replication like HIV does, it gives rise to a novice army of pathogens attacking the human system. HIV-1 is highly pathogenic because it is a new virus, its ultra-high mutations and imbalance caused in the dynamic relationship of host and microbe (3).
Since HIV-1 was discovered by Luc Montagnier and Robert Gallo in 1981(4), the virus co-relations has been studied scrupulously and it has been noted that in HIV-infected individuals, immunodeficiency is unexpectedly related with immune-activation (5). It is evident from the recent study that the immune action is triggered by HIV-1 Envelope which in turn kindle viral replication induced cell-apoptosis there-by promotes the vicious cycle of viral replication and aids disease progression (6). This condition provides easy access to opportunistic pathogens to co-infect. Likewise when scientists were investigating on viral co-infections with HIV-1 they were flabbergasted to find that there are certain microbes which interact and compete for the same host cellular receptors that HIV uses for its early pathogenesis. One of the major opportunistic pathogen that interacts with HIV-1 the same way is herpes virus which was first identified by Vidal (French dermatologist) in 1983 (7). Since then several studies suggested that HHV plays a major role in the pathogenesis and disease progression of HIV-1 due to vast variety of herpes family, sero-prevalence of HHV with HIV and due to it pathogenesis is likewise to HIV. Further we review the interactions of Human herpes viridae with HIV-1 and there implications in its pathogenesis and progression towards AIDS.
Human Herpes Viridae (HHV):
Herpes is a communicable disease. There are 100 or so herpes viruses known to infect animals, out of which eight members are known to cause disease in humans. These human herpesviruses (HHV) can be divided into three sub-families which include HHV-1, HHV-2, VZV (Varicella Zoster Virus) in Alpha-herpesvirinae, CMV (Cytomegalovirus), HHV-6 and HHV-7 in Beta-herpesvirinae and EBV (Epstein - Barr virus) and HHV-8 in Gama-herpesvirinae (8, 9). The primary target cell, site of latency, pathophysiology and mode of transmission of these viruses have been shown in table -1. (10)
Primary cell Target
Site of Latency
Means of Spread
Herpes Simplex Virus-1 (HSV-1)
Oral and/or genital herpes (Predominantly orofacial), as well as other herpes simplex infections
Close contact (sexually transmitted disease)
Herpes Simplex Virus-2 (HSV-2)
Oral and/or genital herpes (predominantly genital), as well as other herpes simplex infections.
Close contact (sexually transmitted disease)
Varicella Zoster Virus (VZV)
Chickenpox and Shingles
Respiratory and close contact (including sexually transmitted disease)
Epstein-Bar Virus (EBV)
B-cells and epithelial cells
Infectious mononucleosis, Burkitt's lymphoma, CNS lymphoma in AIDS patients, post-transplant lymphoproliferative Syndrome (PTLS) nanopharyngeal carcinoma, HIV-associated hairy leukoplakia
Close contact, transfusions, tissue transplant and congenital
Cytomegalo Virus (CMV)
Monocyte, Lymphocyte and Epithelial Cells
Syndrome, retinitis etc.
Roseolo Virus, Herpes Lymphotropic Virus
Sixth Disease (Roseola infantum or exanthema subitum)
Respitory and close contact
disease (roseola infantum or exanthem subitum)
Sarcoma associated herpes virus
and other cells
Multi-centric Castle man's disease.
These viruses have a typical virion structure and share a number of other features. For escaping the host immune system, including interference with different stages of the presentation of viral peptides on the cell surface by class-I human leukocyte antigen (HLA) proteins, herpesviruses demonstrate a number of mechanisms. Within the last 10 years, three members of the herpesvirus family (HHV-6, HHV-7 and HHV-8) have been discovered. Both HHV-6 and HHV-7 cause exanthem subitum, and both seem to be less pathogenic then the other family members of herpes viridae. HHV-8 was discovered by the newly developed technique of representational difference analysis, and was identified in Kaposi's sarcoma (KS) tissue of HIV AIDS patient (11); hence it is believed to be intricately related to HIV. And in the last decade the interaction of herpes viruses with HIV, reveled new strategies in the therapeutic area. Hence, below we review the interaction and existence of all herpes-viruses in HIV infected population worldwide.
Epidemiology: Existence with HIV-1
Numerous studies suggested that opportunistic infections appeared to present the most traditional complications in HIV infected population (12). According to a survey the global prevalence of HIV-1 has stabilized to 0.8% (13); with almost 45 million people worldwide infected with HIV and amongst them more than 75% of all HIV-infected individuals have developed HHV-related symptoms. HAART is however (Highly Active Anti-Retroviral Therapy) proved to be a benediction for HIV positive individuals by increasing their life expectancy and altering the rate of relapse of herpes but it was still impossible to control the disease manifestations (14). Likewise, analogous studies have concluded that there exist a considerable relationship among sexually communicated HIV-1 and Herpes Viruses (HSV) (15). HSV-1 and HSV-2 are the most common co-infections seen in HIV-1 infected individuals. In global context, the epidemiological data suggests 90% to 100% seroprevalence of HSV-1 co-infection while HSV-2 has significantly low seroprevalence; viz, 42% to 100% in HIV infected individuals world-wide ranging from infants to adults till the age of 50 (16). The co-incidence of sharing the common route of transmission through sexual contact by both the viruses supports the belief that the two viruses interact with each other in a significant way. Also, the laboratory demonstration suggests that the genital herpes fuels the risk of transmission and acquisition of HIV by 2 to 4 folds by disrupting the epithelial barrier of the vaginal tissue. Genital herpes is generally caused by HHV-2 while less frequently demonstrated by HHV-1 (17, 18). While the prevalence of other primates of the herpes family also showed significant figures in the cohort of HIV infected population of Southeast Asia. The data showed the incidence of CMV is higher than the other primates with 49%, followed by 47% for HSV & 26% for EBV. VZV has low but significant figures with 32.5% sero-prevalence in South-eastern Asia (14). A study showed 39% of HHV-8 DNA extracted from the HIV sero-positive individuals indicates apparent relationship between HHV-8 and HIV. While a very high percentage of CMV and EBV (85.5% and 81.5%) DNA sequences were found in HIV-1 sero-positive individuals and in comparison the frequency of HSV-1 and HSV-2 sequences in HIV-infected individuals was substantially lower (23.7%) than that of CMV and EBV (19). While in African population, the sero-prevalence of EBV was estimated at 93%-99% in HIV-1 sero-positive cohort with 50% of HHV-6 sero-prevalence (20).
HHV-6 appeared to be one of the cause of acquiring the HIV-1 viral infection while is not affected with the HIV related immune-suppuration (21). The prevalence of HHV-6 DNA in Hodkin's disease and B-cell Non Hodkin's Lymphomas in HIV-infected patients (30% and 6% respectively) was found remarkably lower and similar results were observed in lymphoproliferative disorders from HIV sero-negative patients. HHV-6 prevalence is ranging from 20% to 100% around the world (22), and found in about 36% to 100% of the HIV infected populations (23, 24). In Thailand a study demonstrated high titer values of HHV-6 in individuals with full blown AIDS but strikingly this study has also found no significant difference between the titers of HHV-6 in HIV-1 infected population and HIV-1 non-infected population (25). However, according to another study, HHV-6 is found to be differently interacting with HIV-1 in different parts of the body (21). Likewise, HHV-6 has more than 50% seroprevalence in the retinal tissue of the individuals infected with HIV-1(26) while have more than 85% prevalence in human saliva (27) and occur around 33% in human serum samples (26) and almost nil detection in the breast milk (22). In addition, out of the two variants identified of HHV-6, variant-B was more prevalent than variant-A in general population (21, 28).But contrasting to other cohorts, a study on HIV endemic region of sub-African population showed high sero-prevalence of HHV-6A (86%). The study also present with the information that among the HHV-6 positive fibril patients has high (57%) seroprevalence of HIV-1 then asymptomatic (3%) patients (29). In HIV-1 non-infected patient, the infection of HHV-6 occurs at the infant stage of life i.e. at the age of 6 months and it gets sero-converted into HHV-7 after 24 months of age and remains latent in the body unless gets reactivated due to immunosuppression or transplantation (28). Seroprevalence of HHV-6 reaches >80% in children >2 year while latently present in 98% of the adults in general, worldwide (30).A study on Mexican republican showed 98.5% sero-prevalence (31). While another study from Zürich, Switzerland stated 71.25% prevalence of HHV-7 in Lymph-nodes of AIDS patients (32). HHV-8, also known as Kaposi's sarcoma associated with herpes virus, is a men's disease. In western Africa the sero-prevalence of HHV-8 among HIV positive individuals is
The sero-prevalence of HHV-8 in western Africa is 65% in HIV-1 sero-positive while 23.7% in sero-negative population. A recent review on HHV-8 and related malignancies reported KS in about 15% AIDS population in US. The overall risk of KS in AIDS patients was estimated to be more than 20,000-times greater than that of the general population and 300-times that of other immunosuppressed patients. The transmission of HHV-8 is from homosexual contact is 83.6% in Brazil, among HIV-1 infected individuals while about 1% through men with hemophilia (33, 34).
HIV prevalence in India:
HIV testing became a part of National Family Health survey (NFHS) in 2006 after a decade the first known case of HIV in a female prostitute from Chennai in 1986. The data suggested that 2.5 million people were infected and pursuing life with HIV between the ages of 15 to 49 which is less than half of the previous year. The prevalence of HIV was estimated to be approximately 0.36% with 0.29% in women and 0.43% in men making men more vulnerable than women. However, this data is evident for the incidence of the disease in India putting it in the que after Africa in numbers (35). However, the youth of age 15-24 are least likely to be HIV-positive (0.10%). The third survey of NFHS estimated HIV prevalence separately for six states shown in the table 2 (36).
HIV prevalence rates in India
In India 33.3% of individuals is sero-positive for HSV-1 and 16.6% are sero-positive for HSV-2. Those with both HSV-1 and HSV-2 antibodies are estimated at 13.3% of the population. If we see the comparison in the gender perspective than Indian men are more susceptible for HSV-2 than women, and increasing sero-prevalence of this virus is commensurate with age. In spite of the high prevalence of HIV in India, the sero-prevalence of HHV-8 is much lower than comparable HIV-positive populations in the USA or Africa (37). In Bombay and Tamil Nadu it spread in rampant manner. In Bombay, HIV prevalence has reached 50% in sex workers, 36% in STD patient. Not only rural areas but urban areas are now under the shadow of HIV. In Bombay, sero-prevalence augmented from 2-3% in patients seen in STD clinics in 1990 to 36% in 1994 and in rural areas 3-4% of some populations have an STD. In India, there are an estimated 1-2 million cases of tuberculosis every year (38). TB is the most prevalent form of opportunistic infection in over 60% of HIV cases. With the availability of highly active antiretroviral therapy and treatment and prevention of opportunistic infections, attributes to the soothing of HIV-infected individuals and HIV-related malignancies. As compared with non-HIV-infected individuals, Non-Hodgkin's lymphoma and cervical cancer were found to occur in a higher proportion among the HIV-infected individuals in India. However, the incidence of HIV-related primary central nervous system lymphoma and Kaposi's sarcoma is low in India.
Role of Human Herpesviruses in HIV progression:
HSV-1 & 2: Herpesviruses and HIV-1 are lifelong persistent viruses. Mosca et al. demonstrated the IE genes namely IE110 (ICPO) and IE175 (ICP4) of herpes simplex virus type-1 (hsv-1) significantly enhance the transcriptional activity of LTR region of HIV-1 . IE110 protein, either alone or in combination with the IE175 protein, can activate the HIV LTR. Co-transfection with the IE175 gene alone or with the vmw65 gene (coding for a virion transcription factor) alone did not lead to HIV-LTR activation (39, 40). The pathogenesis of HSV-1 is believed to be start from mouth, although its genital manifestation has also been observed clinically. And on the other hand HSV-2 is found to be a common infection of the lower genital tract. A number of epidemiological studies are evident that a pre-exposure toHSV-2 infection upsurges vulnerability to the procurement of HIV (41); also the observational studies in HIV-1/HSV-2 co-infected individuals have shown that genital HIV-1 shedding and concomitant increase in HIV-1 plasma viral load is markedly increased during clinical HSV-2 reactivations (42). In 2009 Tobian et al. reviewed that increased risk of HIV acquisition associated with HSV-2 infection may be due to the influx of CD8+ T cells and subsequent recruitment of CD4+ T cells expressing CCR5 and immature dendritic cells into areas of inflammation due to HSV-2 infection with both clinical and subclinical reactivation of mucosal lesions of female genital tract (43, 44). These dendritic cells upon co-infection with HIV-1 become highly apoptotic and readily ingested by phagocytic action. Hence on one hand HSV-2 replication is associated with a ten-fold increase in the number of immature dendritic cells expressing DC-SIGN and a three-fold increase in CCR5 expression on CD4+ T cells, two phenomena that might increase susceptibility to HIV-1 while on the other hand depletion of these immature DC cells occurs followed by parallel increased shedding of HSV-2 and HIV-1 in mucosa. Also, increased replication of HSV-2 gives rise to elevated immune response, which in turn increases the susceptibility to HIV-1. Hence it is apparent that HSV-2 opens up a boulevard for HIV-1 pathogenesis by cracking the genital mucosal barrier by manifesting genital lesions, followed by recruiting the HIV susceptible cells like CD-4 expressing CCR5 chemokine receptors (45).
EBV & CMV: It has been observed in HIV-1 infected patients that there are around 20 times more EBV infected B-cells then healthy person. (46)And also due to impairment of T-cell activity by HIV-1, EBV-infected B cells cannot be effectively suppressed as in normal individuals. Although, EBV causes non-Hodkin's lymphomas (47, 48), but it is not that awfully seen till it become an opportunistic infection due to shrinking immunity in HIV-1 infected individuals. The in-vitro studies enlighten that the interaction of EBV with HIV-1 in host cell resulted in the modulation of HIV-1 viral proteins expression (49). In this context Shannon Kenney in 1988, demonstrate that an EBV immediate-early gene product, BamHI MLF1(BMLF1) initiates the expression of a heterologous gene linked to the HIV promoter. He also found that the trans-activating function of this EBV BamHI MLF1 (BMLF1) immediate-early gene product appears to occur at the post-transcriptional level, as low level of protein product was observed as compared to the degree of stimulation of mRNA (50). The Epstein-Barr virus (EBV) immediate-early gene product, BRLF1, trans-activates the human immunodeficiency virus type 1 (HIV-1) long terminal repeat. Deletional analysis demonstrates that BRLF1 transactivation of the HIV-1 promoter does not require the HIV-1enhancer. Thus, the EBV BRLF1 gene product may transactivate by at least two different mechanisms, one mechanism involving certain enhancer elements and another mechanism which is enhancer independent (51). However, HIV viral load and the progression of HIV disease were not affected by primary infection with EBV.
CMV is complexly involved in the pathogenesis of HIV-1; in patients with CMV co-infected with HIV. Epidemiological data is evident for the highest prevalence of CMV in HIV-1 co-infected patients, all over the world. Through several studies scientists revealed the two ways of CMV interaction with HIV-1 viz.; immunosuppression via CMV and transactivation of HIV-1 LTR region by CMV-encoded chemokine receptor (52, 53). HCMV is reported to interact with non-adherent cells popularly known as natural interferon producing cells (NIPC), which produces cytokines. IFN-Å“ is released in response to HCMV infection which is known to cause inflammation of the organs tissues. In turn due to this, macrophages in bulk came to an action and hence are readily available to be infected by HIV-1 by infecting CD-4 cells. IFN-Å“ is of major concern here as the exact role of it is very suspicious. As, in contrast, it is also evident to block monocyte maturation and down-regulate TNF-Å“ which in turn suppresses the immunity as well as HIV-1 replication in pre- HIV infected individuals (54). CMV activation of HIV-1can be carried out even before the establishment of HIV-1 pro-virus into the host-cell genome at transcriptional and post-transcriptional level (52). The immediate-early (IE) gene of cytomegalovirus (CMV) encodes multiple proteins which are translational products of differentially spliced mRNAs (55). Joseph s. Pagano and Andeng - shanghuang in 1989, hypothesized that an interaction between HCMV and human immunodeficiency virus (HIV) may exist at a molecular level and contribute to the manifestations of HIV infection, and demonstrated that the immediate-early gene region of HCMV, in particular immediate-early region 2, trans-activates the expression of the HIV long terminal repeat and increases the mRNA expression through chloramphenicol acetyltransferase assay and hence postulated that the stimulation of HIV gene expression by HCMV gene functions could enhance the consequences of HIV infection in persons with previous or concurrent HCMV infection (53).
HHV-6 & 7: Paulo Luso a virologist at San Raffaele Scientific Institute in Milan, Italy discovered HHV-6 is often found alongside HIV. He believes that HHV-6 increases the pathogenicity of HIV in co-infected individuals. But to confirm this belief, Margolis (senior investigator at NICHD), in 2001 designed an experimental model using tonsil tissue to study the pathogenesis of HIV. HIV-1 generally gains entry into the host cell by binding to the chemokine receptors (such as CCR-3, CCR-5, CXCR-4) expressed by macrophages (a type of white blood cell) (56). Within the spectrum of chemokine receptors mentioned above CCR-5 and CXCR4 are shared with HHV-6 for its virulence; CCR-5 being the major determinant responsible for transmission to host. HHV-6A is evident to encode a chemokine called U83, which is a hyper variable region causing the existence of two different strains of HHV-6; variant A and variant B. These chemokines works on the principle of chemotaxis and attracts the cells to their receptor (57). On the contrary due to the mutations in HIV-1, the above finding is unworthy the virus adapts to use CXCR-4 as a co-receptor instead of CCR-5 and become resistant to CCR-5 binding chemokines (such as CCL-5, U83A), which are intricately involved in creating a hindrance to HIV-1 replication. This phenomenon is typically followed by loss in CD4+T cells which accounts for the evolving virulent strain (58).
HHV-6 helps in higher level of virus replication while U83 (non-spliced) act as an antagonist to CCR5 chemokine which is a common factor for both the viruses to infect the T-cells yet, likewise, another virus of the same herpes family called Human Herpes Virus-7 (HHV-7), proved to be interacting competitively with HIV-1 to infect CD4 cells and so decreases R5 HIV-1 replication (59). Lusso & Margolis in 2006, proposed three mechanisms by which HHV-7 infection resulted in a generalized decrease in the number of potential HIV targets and hence produces an antagonistic effect: mild depletion of CD4 T cells, severe down-regulation of CD4 on the surface of productively infected T cells, and down-regulation of CD4 on uninfected cells (60).
HHV-8: Kaposi's sarcoma herpes virus was first identified and isolated directly from AIDS patients, by Chang Y and et al. in 1994 (61). Kaposis's sarcoma is a cancerous viral disease that is reported more frequent and aggressive in HIV-1 infected individual as compared to classic Kaposis's sarcoma (KS). From the previous data it is elucidated that KS is mediated by cytokines such as IFN-Î³, TNF, IL-6. These cytokines' levels are increased upon co-infection with HIV in PBMCs. However, IFN-Î³ is expressed by CD8+ and CD14+ macrophages which gradually help in developing the AIDS-KS lesions. The virus HHV-8 infects the tissues which in turn activates the PBMCs. These activated PBMCs results in the increased levels of known inflammatory cytokines such as IFN-Î³, TNF, IL-6 upon co-infection with HIV. (62) This inflammation caused by IFN-Î³ in particular increases the cell proliferation in endothelial cells upon interaction and also induces the tumor like spindle formation. However, the cell proliferation is mediated by Tat protein, released upon the acute infection HIV-1.(63) Tat protein stimulates the endothelial cells by binding to the Å“5ß1 and Å“vß3 (integrins that are expressed in response to AIDS-KS infection and acts as the receptor for Tat proteins to invade the cells) after the action of IFN-Î³ to synthesize and release MMP-2 and MMP-9, two enzymes that degrade the basement membrane of endothelial cells and confer invasive properties to cells during angiogenesis (formation of cells) or tumor growth. And this is how AIDS-KS recruits the host cytokines and amend the cellular mechanism to infiltrate and initiate the HHV-8 cell proliferation and relative tumor growth (62).