HIV Treatment Strategies:

See International AIDS Vacinne Initiative

The institution of highly activate antiretroviral therapy (HAART) has witnessed a major impact on immune reconstitution: sustained increased in numbers of circulating CD4 T cells associated with a rapid drop in plasma viral RNA levels. The mechanisms proposed to explain the increase in numbers of CD4 T cells include cellular redistribution from lymphoid tissue, cellular proliferation of peripheral T cell pool, new T cell synthesis from a thymic source and reduced levels of apoptosis. However, despite the efficacy of these medications, treatment-limiting adverse events are frequent.

The following are treatment strategies currently being used against HIV infection.

• inhibit reverse transcriptase (some reverse transcriptase inhibitors are known). One way to do this is to  use nucleotides which lack OH attachment site (AZT, DDI, DDC). problem: every cell has to duplicate its genome and needs DNA building blocks. Viral transcriptase come about that also are able to discriminate the OH nucleotides.
• Protease inhibition HIV protease inhibitors act during the late stage of the HIV-1 viral cycle by inactivating the HIV-1-encoded aspartyl protease and preventing the cleavage of Gag and Gag-Pol proteins, thereby inhibiting the production of mature infectious HIV-1 virions. (Indinavir, Lamivudine,nelphinavir, ritonavir, saquinirir, stavudine) Although not a cure, these drugs have shown reduction of viral RNA. Protease inhibitors cause substantial increases in CD4+ T-cell counts (both naive and memory cells) in HIV-infected patients.
• Antibodies against the virus. A good example of the role that antibodies can play against viruses is hepatitis B where the recombinant hepatitis B surface antigen vaccine induces neutralizing antibodies which are protective against infection.

Indeed, shortly after primary infection in human, HIV-1 stimulates a humoral immune response which results in the production of antibodies directed against most of the viral structural components. .A particular subset of antibodies is directed against HIV-envelope gp120 and gp41, which are the surface (SU) and transmembrane (TM) glycoproteins. It has also been shown that mothers who transmit HIV to their children have fewer neutralizing anti-HIV antibodies when compared to mothers who do not transmit HIV.

US Patent No. 5,459,060, US Patent 5,777,074,US Patent No. 6,008,044,US Patent No. 6,083,504 all assigned to Bioclonetics Incorporated, describes a human monoclonal antibody which binds to a conserved peptide of of gp41 and, as a consequence biologically blocks syncytia formation between HIV-1 virally infected human lymphocytes and uninfected lymphocytes (CD4+ Cells).

However there are a number of problems with this approach due to  the high variability in surface proteins of HIV. This is also why the immune system is not able to control the virus by itself. Research is focusing on invariant regions of the surface proteins of the virus and using these regions as a vaccine.  However, the  ability of the selected immunogen to elicit sufficiently high titers of HIV neutralizing antibodies and the ability of those anti-HIV antibodies to neutralize a broad group of HIV types or isolates still remains a problem

Antibodies directed against conserved epitopes of HIV will likely decrease the mergence of neutralization resistant mutants. Several neutralization epitopes have been identified on the external membrane glycoprotein gp120. These include (a) a region near the amino terminus which has been shown to be important for virus entry; (b) the V3 hypervariable loop; (c) the CD4 binding domain and (d) a region which spans the carboxy terminus of gp120 and the amino terminus of gp41. For example, the "crown" sequence in the V3 loop of gp120 is conserved to a considerable degree. About 30% of North American HIV isolates have the crown sequence designated MN.

• Vacine Therapy: Neutralizing antibodies are elicited by most, if not all, successful vaccines. However, immunogens that are able to elicit neutralizing antibodies to a broad range of primary HIV-1 isolates have not been found. However, a few rare, broadly neutralzing monoclonal antibodies that have been isolated from patients protect against viral challenge in animal models. Their epitopes include regions on gp41, the CD4-binding site of gp120 and part of the carbohydrate masked silent face of gp120. A molecular understanding of the binding of these broadly neutralizing antibodies to their cognate envelope epitopes should facilitate rational HIV-1 vaccine design.

One such broadly neutralizing human antibody 2G12 binds with nanomolar affinity to gp120. This antibody recognizes terminal Manalpha1-2Man-linked moieties, contributed by oligomannose-type sugars that form a cluster on the silent face of gp120. This face is designated "silent" because the oligosaccharides shield potential antigenic epitopes and also because oligosaccharides attached to the viral coate proteins are processed by the host and are, therefore, unlikely to be immunogenic and also because glycosylated proteins are synthesized as a collection of glycoforms in which multiple sugars can be present at a single site, which dilutes any potential antigenic response. Furthemore, carboydrate protein interactions are usually much weaker than protein-protein interactions and restrict antibodies from approaching their expected range of nanomolar binding affinities. Nevertheless, antibody 2G12 binds with high affinity to carbohydrate epitopes on gp120. The proposed mode of binding of 2G12 is reminiscent of one of the suggested mechanisms of multivalent recognition by animal lectins. A C-type lectin, DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin) also binds carbohydrates on the envelope of HIV and facilitates viral infection of CD4+ T cells. 

A human monoclonal Fab fragment (Fab b12) derived from a combinatorial antibody library prepared from bone marrow of a long-term, asymptomatic HIV-1-seropositive donor has also been shown to be potent in the neutralization of HIV-1.

• Entry/Fushion inhibitors: 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.A 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).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-1patients. 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: 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.
• 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.
• Anti-IL-4 therapy:  See HIV abnormalities
• 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.
• Neutralizing antibodies: Another approach is the use of anti-CD4 receptor antibodies as gp 120 surrogates to boost or elicit an in vivo immune response ("active immunotherapy") that includes high titers of HIV neutralizing antibodies. McDougal, J.S., et al., J. Immunology, 137:2937(1986) and Chanh, T.C., et al., PNAS USA 84:3891 (1987).Yet another approach is neutralizing antibodies against the virus. PCT/US02/33165 filed 16 Oct 2002 discloses a novel anti-HIV human monoclonal antibody called X5. The X5 antibody binds to a unique epitope on gp120 that is induced by interaction between gp120 and the receptor CD4 and enhaced by the coreceptor CCR. It shows strong activity at very low levels. see also laboratory of Dimiter Dimitrov .
• Apoptosis: Another approach is to induce apoptosis of cells form HIV-infected patients. In this respect Fasl and TNF may have clinical utility because of their nonselective induction of apoptosis. However, systemic administration of TRAIL/Apo2L 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-γ secretion as well as antigen-specific lysis.
• Nutrition. 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.