See International AIDS Vacinne Initiative See ViroXchange (latest news on HIV and its treatment/trials) Aaron Diamond AIDS Research Center   

Where HIV/AIDS is Prevalent: AIDS Vu HIV prevlaence map  CDC AIDS Atlas  

MedlinePlus  (HIV drugs)    HIV FDA approved medicines    

Prevention & Where to Get Tested: Preexposure prophylaxis for the prevention of HIV Infection guide    CDC Test center Locator

Introduction:

FDA approved drugs for HIV treatment are distributed into six distinct classes: (1) nucleoside-analog resverse transcriptase inhibitors (NNRTIs); (2) non-nucleoside-reverse transcriptase inhibitors (NNRTIs), (3) integrase inhibitors, (4) protease inhibitors (PIs), (5) fusion inhibitors and (6) coreceptor antagonists. (Hazuda “HIV-1 antiretroviral drug therapy, 2012). 

The treatment of HIV-1 infection was revolutionized in the mid-1990s by the development of hihibitors of the reverse transcriptase and protease, two of three essential enzymes of HIV1, and the introduction of drug regimens that combined these agents to enhance, the overall efficacy and durability of therapty. The advent of combination therpay, also known as HAART, was seminal in reducing the morbidity and mortality assocaited with HIV-1 infection and AIDS. (Hazuda “HIV-1 antiretroviral drug therapy, 2012)

PREP  (Preexposure prophylaxis)

PREP is a fixed dose combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC). 

PREP is recommended as a prevention option for sexually active adult MSM (men who have sex with men), adult heteroxexually active men and won and adult injection drug users and who are at substantial risk of HIV acquisition. 

Rental function should be assed at baseline and monitored at least every 6 months for patients who are taking PREP.  Substantial rsik of acquiring HIV infection includes those people who have a HIV positive sexual partner, those with recent bcterial STI, those with a high number of sex partners, history of inconsistent or no condom use and those engaged in commercail sex work. 

HAART Treatment (see outline)

Viral entry and fusion of the HIV-1 envelope with the host cell membrane allow for uncoating of the viral core and initiate a slow dissolution process that maintains protection of the viral RNA genome while permittig acess to deoxyribonucleoside triphosphates (dNTPs) necessary for reverse transcription and provial DNA synthesis. Reverse transcription is a process extending over the next 10 h of infetion. Reverse transcriptase (RT) as the first HIV-1 enzyme to be exploited for antiretroviral drug treatment. RT is a multifunctional enzyme with RNA-dependent DNA polymerase, RNase-H and DNA-dependent DNA polymerase activiteis, all of which are required to convert the single-stranded HIV-1 viral RNA into double-straned DNA. RT is the target for two distinct classes of antiretroviral agents; the NRTIs, which are analogs of native nucleoside usbtrates, and the NNRTIs, which bind to a noncatalytic allosteric pocket on the enzyme. Together the 12 licensed agents in these two classes account for nearly half of all approved anti-retroviral drugs. (Hazuda “HIV-1 antiretroviral drug therapy, 2012)

The final class of approved ARVs, is the HIV01 PIs. PIs block proteolysis of the vrial prolyprotein, a step requried for the production of infectious viral particles. PIs are among the most potent agents developed to date, but are large, peptidelike compounds that generally reuqire the coadministraiton of a “boosting” agent to inhibit their metabolism and enahnce drug levels. Thus, PI containing regimens contain a drug that does not directly contribute to overal antiviral activity. To date, ritonavir (RTV) is the only boosting agent enhancer available for use, although other compoudns are in clinical development. (Hazuda “HIV-1 antiretroviral drug therapy, 2012)

Antibody treatment (See outline)

Inhibition of Complement Regulatory Proteins: 

Like other particles, HIV activates the complement system and becomes opsonized.  To escape complement mediated lysis, HIV has adopted various properties which include the acquision of complement regulatory molecules such as CD46, CD55, CD59 and factor H. (Stoiber, Molecular Immunology 42, 2005, 153-160). High levels of complement and anti-HIV antibody are present in the blood of infected persons and thus one might predict that virions could by lysed by membrane attack complex (MAC) since it is known that virus can be destroyed in this manner. However, during infection with HIV-1 up to 10 million free virions per millilter can be found in the plasma of infected persons, suggesting that in vivo HIV virons may be resistance to complement mediated viroysis. Saifuddin (J Exp. Med, 182, 1995, 501-509) show that glycosylphosphatidylinositol (GPI) linked protiens CD55 and CD59 are present on HIV-1 and provide resistance to complement mediated lysis. Saifuddin also showed that while primary isolates were resistant to lysis in the presence of HIV specific antiboy, antibody to CD59 induced lysis and antibody to CD55 and CD59 induced lysis of cell line derived virus. 

Active Immunization (vaccination)

RV144: is a vaccine regimen that proved to be 31.2% effective at preventing HIV infection. This was the first time an HIV prevented infection. 

mRNA Vaccination:

Zhang et al. (Nature Medicine, December 2021; 2234-2245) discloses that an mRNA vaccine coexpressing membrane anchored HIV1 envelope (Env) simian immunodeficiency (SIV) Gag proteins to generate virus like particles (VLPs) induces antibodies capable of broad neutralization and reduces the risk of infection in rhesus macques. 

The National Institute of Allergey and Infetious diseases has started clinical trials in February 2022 to evaluate the safety and immunogenicity of three different HIV timer mRNA vaccines in healthy, HIV-ninfected adult participants. 

Passive immunization: 

is an efficacious prevention or treatment of certin viral diseases (e.g., varicella-zoster, cytomegalovirus and HPV). Passive immunization of HIV-1 infected individuals has been reported. In these studies, plasma from HIV-1 infected asymptomatic donors was transfused to patients with AIDS. In obht uncontrolled studies, learance of plasma viral p24 antigen was observed and some patients were shwon to have clinical improvement. (Cummins, “Preparation and characterization of an intravenous solution of IgG from human immunodeficiency virus-seropositive donors,” blood, March 1, 1991, 77(5), pp. 1111-1117).

Entry/Fushion inhibitors: 

The first step in the HIV-1 replication cycle, viral entry, is the target for several classes of antiretroviral agents: attachment inhibitors, chemokine receptor antagonists and fusion inhibitors. The HIV-1 envelope gp120/gp41 has affinity for the CD4 receptor and directs HIV01 to CD4+ immune cells. Interaction of the gp120 subunit of the HIV-1 envelope with CD4 is followed by binding to an additional corecetpor, either the CC dchemokine receptor CCR5 of the CXC chemokine receptor CSCR4. The disposition o fthese coreceptors on the surface of lmphocytes and monocyte/macrophages, and coreceptor recognition by the viral envelope, are major determinants of tropism for different cell types. These sequential receptor-binding evens trigger conformational changes in the HIV-1 envelope, exposing a hydrophobic domain on gp41 that mediates fusion with the cellular membrane. The entire entry process is completed within 1 h of virus contact witht he cell. Gp120 and CD4 are target for small molecule and antibody-based attachment inhibitors BMS-378806 and TNX-355, each of which have shown some clinical promise, alhtough neither is approved. (Hazuda “HIV-1 antiretroviral drug therapy, 2012)

Another possibility is to target the gp120/CD4 interaction as by in vivo administration to HIV positive patients of recombinant, soluble CD4 to compete with membrane-bound CD4 receptors for the HIV’s gp120. One problem with this is that CD4 has a half life of about 30 min in serum. One way to overcome this has been to link the CD4 gene to the constant region gene of human IGG1. This hybrid has a longer half life.

Another promosing entry inhibitor are the CCR5 blockers which are now in clinical phases of drug development. There are currently 3 agents in phase 2/3 development that inhibit viral entry by binding to CCR5, disrupting the interaction between the co-receptor and ciral glycoprotein (gp) 120. They are aplavirox (GW-873140), maraviroc (UK-427,857) and vicriviroc (SCH 417690). Maraviroc has not been approved by the FDA. However, because HIV can use other coreceptors such as CXCR4, an HIV tropism test such as a trofile assay needs to be performed. 

Enfuvirtide, which inhibits the fusion of HIV-1 viron membrane with the CD4+ Th2 cell membrane and redues HIV-1 load in blood of patients by 19.96log10 has recently been approved by the FDA for treatment of HIV-1 patients. 

Another new approach is to disrupt the CCR5 gene through the use of zinc-finger nuclease (see for example US Patent Publication No. 2008/0159996.

Integrase Inhibitors: 

The completion of reverse transcription is required to form the viral preintegration complex, or PIC. The PIC, comprised of viral as well as cellular components, is transported to the nuecleus wehre the second essential HIV-1 enzyme, integrase, catalyzes the integration of the viral DNA with the host DNA. Integrase orchestrates three sequence-specific events reuqired for integration, assembly with the viral DNA, endonucleoytic processing of the 3′ ends of the viral DNA, and strand transsfer or joining of the viral and cellular DNA. The newest class of approved ARVs, integrase inhibitors inhibit strand transfer and clock integration of teh HIV-1 DNA into the cellular DNA. (Hazuda “HIV-1 antiretroviral drug therapy, 2012)

Similar to protease and reverse transcriptase activity, integrase function is essential for retroviral infection. Integrase is also a favorable target because the enzyme has no human cellular counterpart. Stilbenedisulfonic acid derivatives which target integrase are described in US Provisional Patent Application 60/849,718 filed October 4, 2006.

Cytokine Therapy

IL-12 therapy: During HIV infection, a strong defect in T cell proliferation and IL-2 secretion, as well as often IFNy production is found in HIV specific T lymphocytes. These defects can be restored at least partially by the addition of IL-12 in vitro.

Inhibitors of NF-kB: 

Mitogens, cyotkines, and environmental stresses activate HIV replication via NF-kB. Indded, deletion of NF-kB binding sites from HIV LTR and the pretratment of cells with chemical inhibitors of NF-B block the LPS-induced HIV LTR transactivation. It has been proposed that part of the immunomodulatory effects of protease inhibitors is due to their blocking of microbial antigen and TNF-alpha induced NF-B activation.

Chemokine antagonists: 

it has been postulated that CX3CL1 (fractalkine recepotr) antagonists should be used for treatment of HIV-infected individuals early in the infection to limit trafficking of infected lymphocytes released from lymph nodes thereby limiting HIV infection.

Toxic Drugs: 

Another approach is the use of soluble CD4 coupled to toxic drugs to target infected cells.

Apoptosis: 

Another approach is to induce apoptosis of cells form HIV-infected patients. In this respect may have clinical utility because of their nonselective induction of apoptosis. However, systemic administration of  to healthy mice has been shown to be safe and to lack cytotoxic effects. TRAIL/Apo2L has been reported to selectively induce cell death in cells from HIV patients, including latently infected CD4+ T cells and macrophages, without deleterious effects on cells from uninfected patients. Current investigations into therapeutic vaccination aimed to induce and expand CD8 cytotoxic T cell responses could take advantage of apoptosis.

DC based therapeutics: 

DCs are able to internalize apoptotic or necrotic cells and present them in association with MHC class I, in a phenomenon called cross-presentation. Based on in vitro and pre-clinical studies, clinical trials of DC immunization in patients with HIV-1 infection are now beginning. An early pilot study demonstrated that infusions of DCs pulsed ex vivo with HLA-A2 restricted epitopes from gag, env, and pol and recombinant gp160 were well tolerated in six HIV-1 infected subjects. Absolute CD4+ T cells counts changed little during the stud and no difference in viral load could be ascribed to the DC based immunotherpay. However, several patients had improved cellular immune responses assayed by antigen specific lymphocyte proliferation, Il2 and IFN-? secretion as well as antigen-specific lysis.

Gene Therapy:  

Researchers at the National Institute of Health are doing something cutting edge. They are conducting trials on taking cells out of HIV infected patients and treating the cells to eliminate CCR5 which is a necessary receptor on the cells for HIV infection. The results so far have been very promising. 

Deficiencies of micronutrients are common in HIV infected persons. There is also a strong association of deficiencies of micronutrients in HIV infection with rapid disease progression and mortality. Further research is required to elucidate the role of micronutrient deficiencies on the course of HIV infection. However, current knowledge supports the use of routine multivatamin and trace element supplement as adjuvant to conventional antiretroviral drug treatment as a relatively low-cost intervention.

Histone deacetylase (HDAC) inhibitors:

Research has shown that histone deacetylase (HDAC) inhibitors can activate cells that are latently infected with HIV, making them more visible to the immune system. 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. Argos therapeutics is involved in such studies.