AIDS appeared in 1981, Luc Montagnier from France and Robert Gallo from the United States, discovered the virus, now known as Human Immunodeficiency virus (HIV), and the disease known as acquired immunodeficiency syndrome (AIDS). HIV enters the body through mucosal sites infecting macrophages, dendritic cells, and CD14+ T cells, distributing the virus throughout the lymphatic system . HIV typically attacks T4 lymphocytes, which have a CD4 receptor molecule on their surface, as well as macrophages, which also possess a CD4 receptor. CCR5 and CXCR4 are chemokines receptors that allowthe entry of HIV in T-cells, macrophages, and can lead to the activation of neutrophils, monocytes, lymphocytes, basophils, and eosinophils. The two main viral glycoprotein that anchor to CD4+ cells are gp120/gp40. Specifically, gp120 binds to CCR5/CSCR4 and allows for the fusing of the virus 
HIV and the brain:
The central nervous system (CNS) is the most protected organ in the body, the blood-brain barrier (BBB) is a very selective permeable membrane barrier that separates circulating blood from the CNS [3, 4]. The BBB is made of brain microvascular endothelial cells; tight junction proteins (e.g. Claudins, Occludin, ZO-1) connect these cells with a very high resistance of about 1000 Ωcm−2 . Endodethial cells lay on a basal lamina and communicate with astrocytes and pericytes . HIV enters the brain, early during the infection, and establishes its lifelong persistence . In regards to how it enters the CNS, there are different ways in which HIV can access the brain. This includes passing through blood-brain barrier, the choroid plexus, and CSF . However, free HIV can cross the BBB through the opening of tight junctions, infecting both microglial cells and macrophages, which are known to express the CD4 receptor and CCR5 chemokine receptor [7-9]. The CNS is HIV-infected within 2 weeks after exposure. The entry of the virus is dependent on peripheral HIV-infected monocytes/macrophage carriers or by direct HIV penetration of BBB . Monocytes/macrophages that infiltrate the brain from the bone marrow play a significant role in the HIV infection . Other types of cells that are also infected are astrocytes. Even though as few as 5% are infected, the function of the BBB is still compromised. This has been shown both in vivo and in vitro . Inflammation in the brain might play an important factor in the function of astrocytes in the BBB, which might also lead to the failure in regulating BBB integrity, and neurotransmission [8, 10].
Microglial and astrocytic chemokines (e.g. MCP-1), may be regulating access of peripheral blood mononuclear cells through the BBB. Samples of infected humans with HIV and Simians infected with SIV, show that lymphocytes and monocytes were able to get into the brain .
Adhesion molecules and increased expression of vascular-adhesion molecule-1 (VCAM-1), may also play a role in cellular migration to the brain. In vitro experiments show that HIV increases adhesion molecule expression, together with monocytes across culture endothelial cells, and affects the expression of cytokines and interferon signaling in endothelial cells. It is known that HIV infection leads to the release of cytokines, and chemokines, which can exacerbate the malfunction of the BBB. It is suggested that TNF-a can create a route for HIV to enter the brain. HIV-1 proteins such as tat and gp120 can cross the blood brain barrier by adsorptive endocytosis . Neuronal cells lack CD4 receptors, and as a result, are not infected. However, viral proteins, cytokines and chemokines released from infected cells in the CNS can lead to HIV-associated neuropathology [3, 8].
HIV efflux transporters
Efflux transporters, including P-glycoprotein (ABCB1/P-gp1), the breast cancer resistance protein (BCRP, ABCG2) and multidrug resistance protein family (MRP. ABCC family) play an important role in the lack of penetration to the brain [9, 12]. These efflux transporters are found in the apical side of the membrane in the BBB, facing the circulating blood. These efflux transporters can send “foreign” substances back into the blood, preventing from penetrating the brain. Different types of ART are substrates to P-gp1 including HIV protease inhibitors, nucleoside reverse transcriptase inhibitors (e.g. abacavir) the chemokine CCR5 coreceptor antagonist maraviroc, and the HIV integrase inhibitor raltegravir . As a result, there is an increase of P-gp1, decreasing anti-retroviral efficacy in the brain . Other anti-retroviral drugs that increase P-gp1 expression are ritonavir, atazanavir and saquinavir [12, 13]. In addition, it has been shown that HIV infection, especially patients with HIV-endocephalitis (HIVE) increases the release of inflammatory cytokines, such as TNF-a, interferon, and IL-1B, therefore increasing Pgp-1 expression in glial cells .
The first anti-retroviral drug to be used for HIV treatment was azidothymidine (AZT) or brand name Retrovir, discovered by Jerome Horwitz. The current anti-retroviral therapy is classified into six drug groups, which are all based on the HIV life cycle. The six classes are: nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion and entry inhibitors, pharmacokinetic enhancers, and integrase strand transfer inhibitors (INSTIs) .
In 2015, the four international guidelines (IAS, DHHS and EACS, WHO) recommended treating every HIV-infected patient, regardless of their CD4 status with ART . Early ART treatment has low risks of morbidity and decreased size of HIV reservoirs .
Guidelines on antiretroviral therapy for HIV-infected naïve patients
The guidelines on antiretroviral therapy for HIV infected patients indicates that all patients should receive treatment, regardless of the CD4+ cell count [15, 16]. START (Strategic Timing of Antiretroviral Treatment) has shown that immediate therapy in patients with CD4+ cell counts above 500/µl showed a decrease of 57% AIDS-related morbidities, and death . Antiretroviral drugs have shown to have positive effects in individuals with >350 CD4+ cells/µl, with 80% of individuals receiving antiretroviral therapy with more than 350 CD4+ cells/µl having an increase to more than 750 CD4+ cells/µl within 4 years . Although, an early start on antiretroviral therapy has shown to be effective, treatment is highly recommended for patents with count between 350-499 CD4+ cells/µl or less than 350 CD4+ cell/µl.
The Food and Drug Administration (FDA) has approved different types of antiretroviral drugs including nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), a fusion inhibitor (FI), a CCR5 antagonist and an integrase strand transfer inhibitor (INSTIs). The current therapy for naïve patients is two NRTs together with INSTI, an NNRTI, or a PK-enhanced PI . Naïve patients with advanced HIV infection are recommended to take boosted protease inhibitors . In October 17, 2017 the U.S. Department of Health and Human Services, the new regimen for HIV treatment is “Dolutegravir/abacavir/lamivudine—only for patients who are HLA-B*5701-negative (AI); Dolutegravir plus tenofovir/emtricitabine; Elvitegravir/cobicistat/tenofovir/emtricitabine; Raltegravir plus tenofovir/emtricitabine for tenofovir disoproxil fumarate, AII for tenofovir alafenamide)”. (Dolutegravir is a relatively a new integrase inhibitor, it differs from other integrase inhibitors, since it can inhibit entrance of transcribed HIV DNA into the host’s DNA ).
In regards to the permeability of anti-retroviral drugs, these drugs have to pass through simple diffusion into the CNS, they have to be lipid soluble . It has been shown that NRTI’s low molecular weight and low rates of protein binding, make them the best candidates to penetrate the cerebrospinal fluid (CSF) . A study demonstrated that zidovudine, stavudine, didanosine and lamivudine have a good penetrability in the CNS . Lamivudine (3TC) has been shown to be absorbed from the blood into the choroid plexus, through the digoxin-sensitive transporter .Tenofovir (TDF) has a low concentration in the CSF, which suggests that the mechanism of transport could be passive or limited active. Interestingly, TDF precursor PMPA can accumulate in the choroid plexuses, indicating the existence of a transporter in the choroid plexus. Efavirez (EFV) also has limited access to the CSF, and has been shown that EFC can induce P-glycoprotein (PGP). Protease inhibitors concentrations are expected to be highly concentrated in the brain because of their excellent lipid solubility; however, many PIs are substrate for PGP and have a high plasma protein binding. On the other hand, Ritonavir, has been shown to increase penetrability in the CSF . Also, concentrations of darunavir (DRV) have been found in the CSF. Finally, Raltegravir (RGV) has been shown to be penetrable into the CSF. A study demonstrated that 21 samples had RGV levels above the IC50, with median concentration in the CSF being 14.5 ng/ml .
Preventive healthcare includes condom use, anti-retroviral treatment, pre-exposure prophylaxis (PrEP), circumcision in men and HIV counselling and testing . PrEP is the use of antiretroviral treatment, for non-HIV infected individuals, who are in risk of HIV infection . High risk individuals include men who have sex with men (MSM), high-risk heterosexuals and injection drug users (IDUs). PrEP drug selection comes from approved anti-retroviral drugs that are being used by HIV-infect individuals. There is approximately about 30 drugs/drug combinations approved by the U.S. Department of Health and Human Services (DHHS) . There are two types of drugs, (Preintegration vs. Postintegration). Preintegration drugs include chemokine receptor antagonists, nucleoside, nonnucleoside analog reverse-transcriptase inhibitors, and integrase inhibitors. Postintegration drugs include protease inhibitors, and maturation inhibitors. Preintegration drugs are more applicable than postintegration drugs, because PrEP drugs need to be able to reach mucosal tissues and have to be low protein-bound compounds, such as nucleoside-analog reverse-transcriptase inhibitors (NRTIs) .
In 2012, the US Food and Drug Administration approved Truvada (tenofovir + emtricitabine), the first drug to decrease the risk of HIV infection [24, 26]. Tenofovir disoproxil fumarate (TDF) and Emtricitabine (FTC) are reverse transcriptase inhibitors. TDF has a long half-life, which allows only one daily dose, and has a very low interaction with other drugs [27, 28]. The concentrations of TDF and FTC have been measured in different mucous tissues including the cervix, vagina and rectum. The concentration of TDF was 100 fold higher in the rectum than in the cervix or vagina. However, FTC was 10 fold higher in vaginal and cervical tissue than in rectal tissues. A study demonstrated that Truvada protected 4 out of 6 simian/human immunodeficiency virus (SHIV) infected macaques, that were co-infected with sexual transmitted infections (STIs). Although Truvada has been shown to be a promising drug to prevent HIV infection, another clinical study showed that only about 50-80% of individuals taking PrEP had detectable tenofovir . Cabotegravir is an integrase inhibitor with a long half-life, is in phase2a trials, and has the potential of been administered once every three months. Recent studies done in macaques (Macaca mulatta), demonstrated that administration of cabotegravir (50mg/ml) every 4 weeks had detectable levels of the drug. These results were similar to that of the human plasma concentration of cabotegravir after 12 weeks of administration .
Rilpivirine long acting (RPV-LA), with a potential as pharmaceutical for PrEP. (remove Rilpivirine) is a nonnucleoside reverse-transcriptase inhibitor. It is a parenteral formulation that has been shown to have long lasting levels of RPV in plasma, vaginal tissue (VT) and cervicovaginal fluid (CVF) in women and in the rectal tissue (RT) in men . Although PrEP has high expectations to prevent infection in individuals with increased risk of contracting HIV, several articles have discussed the use of PrEP, as motivation to have unprotected sex . Many health care providers refrain from prescribing PrEP in order to prevent such behavior . There is also a concern for the development of drug resistance in PrEP users, but there are not many reports of drug resistance in this group of people . A recent study suggests that there is a higher risk of drug resistance from treatment failure of TDF/FTC than individuals using TDF/FTC PrEP . Individualized medicine could be the solution to prevent ART failure and resistance .
Microbicides are important to prevent infection in cervicovaginal and colorectal mucous membranes . A study demonstrated that anti-HIV microbicides could be another method to prevent HIV transmission. CAPRISA 004 (tenofovir vaginal gel) phase2b partially prevented HIV transmission in women . A second method of PrEP is dapivirine, which is a vaginal ring. Early in 2016, the Ring study and ASPIRE demonstrated that monthly use of dapirivirine prevented HIV infection in women [35, 36]. Although dapivirine is a potent inhibitor of HIV, it is not soluble in aqueous solutions. A recent study has developed dapivirine-loaded, poly(ethylene oxide)-coated poly(epsilon-caprolactone) (PEO-PCL) nanoparticles, which were able to be distributed into the mucosal tissues of mice (vagina and lower uterus) . A third microbicide is an active dendrimer in VivaGel (SPL7013) from Starpharma, Australia. This dendrimer blocks viral entry by interacting with gp120 and it has been shown to decrease HSV-1/2 in vitro [35, 38].
Anti-retroviral drugs and brain toxicity
Individuals with HIV-associated dementia (HAD) have difficulties with cognitive tasks such as memory, attention, motor function loss, and behavioral and emotional difficulties . A study done in women demonstrated that HIV+ women had decrease activity of the hippocampus during encoding and increase activity during recognition, indicating memory loss by the Hopkins Verbal Learning Task (HVLT) . Anti-retroviral drugs may improve patients outcome, however, HIV-associated dementia can still progress under ART. HIV-associated neurocognitive disorders (HAND) has three sub-categories 1) asymptomatic neurocognitive impairment (ANI); 2) mild neurocognitive disorder (MND) and 3) one of the most severe forms HAD . Since the use of ART, there have a decrease of less serious categories of HAND such as ANI and MND . A 4 year study demonstrated that HIV+ individuals showed a decreased of HAND progression when under ART . Additionally, another study demonstrated that HIV infected individuals had decrease “cortical thickness in the orbitofrontal cortex, cingulate gyrus, primary motor and sensory cortex, temporal, and frontal lobes” compared to non-HIV infected individuals. Concluding that early use of anti-retroviral drugs allows for early protection of HIV-induced neuro-degeneration .
1. Sherman, I.W., Drugs that changed the world : how therapeutic agents shaped our lives, ed. ProQuest and C.S.A. ProQuest. 2017: Boca Raton : CRC Press, Taylor & Francis Group.
2. Brown, A., Understanding the MIND phenotype: macrophage/microglia inflammation in neurocognitive disorders related to human immunodeficiency virus infection. Clin Transl Med, 2015. 4: p. 7.
3. Zhang, Y.L., et al., Blood-brain barrier and neuro-AIDS. Eur Rev Med Pharmacol Sci, 2015. 19(24): p. 4927-39.
4. Romo-Gonzalez, T., A. Chavarria, and H.J. Perez, Central nervous system: a modified immune surveillance circuit? Brain Behav Immun, 2012. 26(6): p. 823-9.
5. Castro, V. and M. Toborek, The Blood-Brain Barrier, in Neuroinflammation and Neurodegeneration, P.K. Peterson and M. Toborek, Editors. 2014, Springer New York: New York, NY. p. 3-28.
6. Gartner, S., HIV infection and dementia. Science, 2000. 287(5453): p. 602-4.
7. Mzingwane, M.L. and C.T. Tiemessen, Mechanisms of HIV persistence in HIV reservoirs. Reviews in medical virology, 2017.
8. Calcagno, A., et al., Blood Brain Barrier Impairment in HIV-Positive Naive and Effectively Treated Patients: Immune Activation Versus Astrocytosis. J Neuroimmune Pharmacol, 2017. 12(1): p. 187-193.
9. McRae, M., HIV and viral protein effects on the blood brain barrier. Tissue Barriers, 2016. 4(1): p. e1143543.
10. Ralay Ranaivo, H., et al., Albumin induces upregulation of matrix metalloproteinase-9 in astrocytes via MAPK and reactive oxygen species-dependent pathways. J Neuroinflammation, 2012. 9: p. 68.
11. Kaul, M., G.A. Garden, and S.A. Lipton, Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature, 2001. 410(6831): p. 988-94.
12. Namanja-Magliano, H.A., et al., Dual inhibitors of the human blood-brain barrier drug efflux transporters P-glycoprotein and ABCG2 based on the antiviral azidothymidine. Bioorg Med Chem, 2017. 25(19): p. 5128-5132.
13. AIDSinfo in a U.S. government source for information on HIV/AIDS treatment, p., and research, AIDS info Glossary of HIV/AIDS-Related terms. 2015.
14. Yoshimura, K., Current status of HIV/AIDS in the ART era. J Infect Chemother, 2017. 23(1): p. 12-16.
15. Sacktor, N., et al., Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology, 2016. 86(4): p. 334-40.
16. Fehr, J., et al., Reasons for not starting antiretroviral therapy in HIV-1-infected individuals: a changing landscape. Infection, 2016. 44(4): p. 521-9.
17. Palella, F.J., Jr., et al., CD4 cell count at initiation of ART, long-term likelihood of achieving CD4 >750 cells/mm3 and mortality risk. J Antimicrob Chemother, 2016. 71(9): p. 2654-62.
18. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. 2016.
19. Slama, L., et al., Efficacy and safety of once-daily ritonavir-boosted atazanavir or darunavir in combination with a dual nucleos(t)ide analogue backbone in HIV-1-infected combined ART (cART)-naive patients with severe immunosuppression: a 48 week, non-comparative, randomized, multicentre trial (IMEA 040 DATA trial). J Antimicrob Chemother, 2016. 71(8): p. 2252-61.
20. Hightower, K.E., et al., Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob Agents Chemother, 2011. 55(10): p. 4552-9.
21. Nau, R., F. Sorgel, and H.W. Prange, Lipophilicity at pH 7.4 and molecular size govern the entry of the free serum fraction of drugs into the cerebrospinal fluid in humans with uninflamed meninges. J Neurol Sci, 1994. 122(1): p. 61-5.
22. Ene, L., D. Duiculescu, and S.M. Ruta, How much do antiretroviral drugs penetrate into the central nervous system? J Med Life, 2011. 4(4): p. 432-9.
23. Maartens, G., C. Celum, and S.R. Lewin, HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet, 2014. 384(9939): p. 258-71.
24. Adams, L.M. and B.H. Balderson, HIV providers’ likelihood to prescribe pre-exposure prophylaxis (PrEP) for HIV prevention differs by patient type: a short report. AIDS Care, 2016. 28(9): p. 1154-8.
25. Heneine, W. and A. Kashuba, HIV prevention by oral preexposure prophylaxis. Cold Spring Harb Perspect Med, 2012. 2(3): p. a007419.
26. US Food and Drug Administration. FDA News Release: FDA approves first drug for reducing the risk of sexually acquired HIV infection. 2013.
27. Grim, S.A. and F. Romanelli, Tenofovir disoproxil fumarate. Ann Pharmacother, 2003. 37(6): p. 849-59.
28. National Center for Biotechnology Information. PubChem Compound Database; CID=60877. 2016.
29. Radzio, J., et al., Combination Emtricitabine and Tenofovir Disoproxil Fumarate Prevents Vaginal Simian/Human Immunodeficiency Virus Infection in Macaques Harboring Chlamydia trachomatis and Trichomonas vaginalis. J Infect Dis, 2016. 213(10): p. 1541-5.
30. Andrews, C.D. and W. Heneine, Cabotegravir long-acting for HIV-1 prevention. Curr Opin HIV AIDS, 2015. 10(4): p. 258-63.
31. Jackson, A.G., et al., A compartmental pharmacokinetic evaluation of long-acting rilpivirine in HIV-negative volunteers for pre-exposure prophylaxis. Clin Pharmacol Ther, 2014. 96(3): p. 314-23.
32. Calabrese, S.K. and K. Underhill, How Stigma Surrounding the Use of HIV Preexposure Prophylaxis Undermines Prevention and Pleasure: A Call to Destigmatize “Truvada Whores”. Am J Public Health, 2015. 105(10): p. 1960-4.
33. Mayer, K.H. and C. Beyrer, Antiretroviral chemoprophylaxis: PROUD and pragmatism. Lancet, 2016. 387(10013): p. 6-7.
34. Parikh, U.M. and J.W. Mellors, Should we fear resistance from tenofovir/emtricitabine preexposure prophylaxis? Curr Opin HIV AIDS, 2016. 11(1): p. 49-55.
35. das Neves, J., et al., Nanomedicine in the development of anti-HIV microbicides. Adv Drug Deliv Rev, 2016. 103: p. 57-75.
36. microbicides, I.P.f., Two Large Studies Show IPM’s Monthly Vaginal Ring Helps Protect Women Against HIV. 2016.
37. das Neves, J., et al., Biodistribution and pharmacokinetics of dapivirine-loaded nanoparticles after vaginal delivery in mice. Pharm Res, 2014. 31(7): p. 1834-45.
38. Gong, E., et al., Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses. Antiviral Res, 2005. 68(3): p. 139-46.
39. Katz, M.H., HIV Infection & AIDS, in Current Medical Diagnosis & Treatment 2017, M.A. Papadakis, S.J. McPhee, and M.W. Rabow, Editors. 2016, McGraw-Hill Education: New York, NY.
40. Maki, P.M., et al., Impairments in memory and hippocampal function in HIV-positive vs HIV-negative women: a preliminary study. Neurology, 2009. 72(19): p. 1661-8.
41. Heaton, R.K., et al., HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol, 2011. 17(1): p. 3-16.
42. Sacktor, N., Changing clinical phenotypes of HIV-associated neurocognitive disorders. J Neurovirol, 2017.
43. Sanford, R., et al., Regionally Specific Brain Volumetric and Cortical Thickness Changes in HIV-Infected Patients in the HAART Era. J Acquir Immune Defic Syndr, 2017. 74(5): p. 563-570.