**2. Link between HIV and MS risk**

**1. Introduction**

188 Trending Topics in Multiple Sclerosis

cell activation seem to play a significant role [4].

mental and epigenetic factors are at higher risk (**Figure 1**) [8, 9].

Multiple sclerosis (MS) is a complex, debilitating neurologic disease characterized by demye‐ linationof axons inthebrainandspinal cordandcausedbyanimmune attackagainstthemyelin sheath. The disease is highly prevalent in North America and Europe (>100/100,000 inhabi‐ tants). According to the recently revised 2013 Atlas of MS published by the World Health Organization(WHO)andMultipleSclerosisInternationalFederation(MSIF)(http://www.atlas‐ ofms.org), the prevalence rate of 5–20 per 100,000 has been reported for India. Clinically, MS is characterized by a broad spectrum of symptoms [1]. It has autoimmune and inflammatory components, with intense effects on the communication between nerve cells within the brain and spinal cord [1]. The different types of MS vary in terms of severity, prevalence, and degree of progression [2, 3]. The most common phenotype is relapsing remitting (RR) MS, followed by secondaryprogressive (SP) andthenprimaryprogressive (PP).Lessprevalentphenotypeshave also been reported [2]. MS pathology is characterized by inflammatory plaques caused by demyelination of axons in the central nervous system (CNS). Due to the presence of immuneinflammatory characteristics in MS, treatments targeting T lymphocyte and natural killer (NK)

With intangible and enigmatic etiology having both genetic and environmental backgrounds, MS offers a profound conundrum. Yet, despite incomplete understanding of the basic mechanisms behind its pathogenesis, a growing body of evidence suggests heterogeneous etiology of MS with multiple environmental factors contributing to its development [5–7]. Various studies suggest that intricate interactions between genetic factors and environmental factors elicit it; thus, genetically susceptible individuals who encounter a number of environ‐

**Figure 1.** Multiple sclerosis as a complex neurological condition affecting CNS: The etiology of MS is unknown and enigmatic; however, it has a profound role of numerous environmental and genetic components, and multiplex inter‐ actions between them lead to its development, thus making it a multifactorial and polygenic heterogeneous disease.

Some risk factors, which have been studied in various populations, include geographic location [10, 11], wheat consumption [11, 12], dairy product consumption [13, 14], fish intake [15], animal fat intake [15], high ultraviolet radiation [16–18], vitamin D deficiency [19], and The epidemiology of MS shows a latitudinal gradient, and its risk is governed by genetic predisposition as well as local environmental conditions (**Figure 1**). Even though its etiology remains uncertain, quite a few studies have suggested involvement of a virus in its pathogen‐ esis. For example, the association between genetic and infectious components in MS develop‐ ment is suggested by the HERV, which constitutes about 8–30% of the human genome with approximately 98,000 elements [29]. Until 2005, however, no HERVs capable of replication had been identified, only traces of original viruses were identified [30]. were identified. Only one family of HERV viruses has been active, the HERV-K family, comprising <1% of total HERV elements [29, 30]. This family is a candidate for playing a fundamental role in MS pathophysi‐ ology. Evidence for this role includes studies that have shown activation of T-cell response against HERV in individuals infected with HIV [31]. This has formed the much needed ground for alternative drug therapy targeted against HERV for elimination of HIV, and it might therefore aid in using HERV proteins as markers for drug designing instead of frequently mutating HIV antigens. One of the HERV proteins reported to be expressed in the active lesions of MS is the MS-associated retrovirus envelope protein (MSRV-Env) [32–34]. There is accu‐ mulating evidence suggesting an inverse association between HIV and MS, and large-scale epidemiological studies have supported this notion. Studies have found significantly lower prevalence of MS in people with HIV infection [26]; moreover, there has been only a single case report of MS treatment with antiretroviral drugs in an HIV patient.

With the help of population-based databases, a recent study demonstrated reduced incidence of MS in HIV patients; however, due to a smaller sample size, it proved statistically insignifi‐ cant [26]. Gold et al. [25] investigated a much larger sample and revealed a statistically significant negative relationship between HIV and MS, reflecting a protective effect of HIV on MS. Still unclear is the exact mechanism behind this association. The protection HIV provides against MS may be mediated by suppression of the immune system due to chronic HIV infection and antiretroviral medications, thus preventing MS progression or treating it completely (**Figure 2**). To date, it is not known whether HIV *per se*, application of antiretroviral therapy (ART), or a combination of the two diminishes MS symptoms. The most plausible explanation for this protective effect may be HIV-induced immunodeficiency targeting a wide continuum of immune cells and signal transduction pathways involved in MS pathogenesis. Alternatively, antiretroviral medications used against HIV may target other viruses involved in MS pathogenesis such as, HERV and herpes.

**Figure 2.** Protective inverse relationship between MS and HIV: HIV infection leads to reduced MS risk, which may be attributed to constant suppression of the immune system by HIV-induced immunodeficiency targeting diverse spec‐ trum of immune cells and signal transduction pathways involved in MS pathogenesis, and/or antiretroviral drugs used to treat the infection, thus preventing MS progression or treating it completely.

The big puzzle of whether and when to start HIV therapy in MS patients remains blurred. Previous studies based on case report and data linkage studies presumed that protective infection was conferred against MS development due to ART treatment rather than HIV infection *per se*. However, in neither case has systematic description been offered about the individuals who were treated with ART and those who were not [27]. There are still different opinions on early [35] and late treatment options due to different aspects such as side effects and drug resistance [36]. Therefore, no clear-cut approach exists on starting ART. In these studies, nothing has been mentioned about exposure to antiretroviral medications and its duration [27]. Moreover, HIV and MS are often misdiagnosed due to the presence of MS-like symptoms in HIV; therefore, focus should be on targeted treatments of MS patients with HIV and vice versa. To fully understand the mechanism behind the apparently MS-protective phenotype of HIV infection, the most plausible research approach would be analysis of data on HIV patients with MS or vice versa and the details on influence of cotreatment with antiretroviral medications and disease-modifying treatments (DMTs).

Due to the presence of immune-inflammatory characteristics in MS, treatments targeting T lymphocyte activation may play a significant role. There is growing evidence that favors suppression of MS pathology by employing anti-HIV therapy, and it has prompted one trial in MS patients for the drug Raltegravir (Isentress) [37] used in HIV treatment and also an immunoglobulin G4 monoclonal antibody called GNbAC1 [4, 38–40] against HERV proteins. The association between HIV and MS can be exploited to replace conventional treatment options for MS by formulating new safe, effective, and long-term therapeutic alternatives. Further investigations are mandatory to provide a deeper insight into the mechanism of action for HIV/ART on MS risk, and this can be fulfilled by carrying out large-scale clinical, molecular, as well as epidemiological studies.
