OVERVIEW OF HAART, ART AND HIV-1 RESERVOIR

HAART is the acronym for highly active antiretroviral therapy. The term combination antiretroviral therapy (cART) can also be used synonymously with cART. Thus, HAART can also be referred to as cART. For the purposes of this review, the term HAART will be used. HIV is a highly mutating viral pathogen; and thus single therapies or monotherapies directed at the virus in vivo might end up not producing the desired clinical outcome or prognosis – since the targeted virus might change and not respond to the therapy. In addition, monotherapy in HIV treatment and management processes might also contribute and lead to the development and resistant strains of the virus. Despite this, the bioavailability of cART/HAART in PLHA is critical to measure the prognosis of the individual especially with the notable mutation rate of HIV. But how is HAART measured in PLHA? The effect of highly active antiretroviral therapy (HAART) in the treatment of HIV infection is usually measured by survival, CD4 lymphocyte counts, HIV-1 RNA viral load testing, and the occurrence of opportunistic infections.

Having these parameters in mind, and as a way of determining the in vivo efficacy of HAART in PLHA, it is also important to determine and evaluate the bioavailability of these drugs in several different anatomical sites especially those tissues that have been previously characterized or are currently emerging anatomical reservoir sites for HIV-1 such as adipose tissues. To effectively treat HIV and suppress the viral load of the infection to undetectable limits (<50 copies/ml), a combination of antiretrovirals that target different and specific stages of the HIV replication stages or processes are often used clinically in combination; and these agents are administered to PLHA as a regimen to achieve HIV suppression. However, HIV in its ingenuity and high mutational rate still finds a way to come out once in a while from its hiding place and cause one or two infections even in people on cART/HAART. The drugs used in HAART target four (4) different steps in the HIV replication cycle including the viral entry step, reverse transcription step, integration step and maturation step. The different antiretroviral agents used for HIV treatment are usually divided into four (4) classes of agents that are used in HAART; and these are briefly summarized.

  1. Nucleotide/nucleoside reverse transcriptase inhibitors (NRTIs): Reverse transcriptase (RT) enzyme is an important enzyme in HIV replication. RT helps to reverse transcribe the HIV RNA into HIV proviral DNA (in a process known as reverse transcription), which can carry out the normal process of the central dogma of molecular biology (i.e. DNA-RNA-Protein). Without RT, it will be impossible for HIV to replicate in vivo; and thus the virus may not be a serious threat to humanity as it is now. Reverse transcription is usually the first thing the virus must do once it enters a host cell in order to maintain its continued perpetuation or existence in the infected host cell and elsewhere. NRTIs are antiretrovirals that target the reverse transcription step that converts the viral genomic RNA into linear double stranded DNA. Typical examples (generic name shown) include zidovudine, emtricitabine, tenofovir alafenamide, tenofovir, lamivudine and abacavir to mention a few.
  2. Non-nucleotide reverse transcriptase inhibitors (NNRTIs): NNRTIs like NTRIs target the reverse transcription step that converts the viral genomic RNA into linear double stranded DNA. Examples include (generic name shown) efavirenz, nevirapine, etravirine and rilpivirine.
  3. Protease inhibitors (PIs): Protease are other important enzymes that help to breakdown or cleave the polyproteins produced during HIV replication into their respective constituent and smaller proteins required for the formation of a new virion. Protease is critical for the maturation of viral particles that bud out from infected host cells Typical examples include (generic name shown) indinavir, ritonavir, saquinavir, tipranavir and atazanavir.
  4. Integrase inhibitors: Integrase enzyme helps the HIV genome to be successfully integrated into the genome of the infected host cell. Without this enzyme, HIV replication may not proceed further. Integrase inhibitors can also be called integrase strand transfer inhibitors (INSTIs), and they block integrase strand transfer activity that is required to insert viral DNA into a host cell chromosome. Examples include (generic name shown) raltegravir, dolutegravir and elvitegravir.

It is no doubt that the persistence of HIV infection in PLHA, and the reason for the perpetuated viral rebound experienced in these individuals is mostly attributable to the lurking, preservation and protection of latent strains of HIV-1 and/or SIV (in non-human primates) in certain cellular and anatomical sites of the body as has been already highlighted in this review. These cellular and anatomical reservoir sites including lymph nodes, CD4+ T cells, spleen and macrophages to mention a few continue to serve as repertoire from which the peripheral circulation is replenished with infectious virus that causes the viral rebound (or new infections) experienced in PLHA even in the face of HAART or cART. Thus, the current HAART/cART should be re-engineered to target and possible enter both cellular and anatomical reservoir sites of HIV in order to ensure adequate antiviral activity in vivo.

More so, they should be able to maintain appropriate intercellular concentration and reach the bioavailability level required to possibly purge the reservoir sites of the virus. It is therefore important that the current ongoing reserve on finding a functional cure for HIV takes into account the different pharmacological differences that exist amongst these cellular and anatomical sites since certain antiretroviral drugs penetrate some tissues or cells more efficiently than they do in other sites where a pharmacological barrier or wall has been constituted, maybe due to differences in drug concentrations relative to the cells membranes and other physiological and metabolic processes.  Though HAART has contributed a great deal towards viral suppression and HIV-1 control in PLHA, it is still important for new drug targets to be rediscovered for novel drug targets; and also, further drug developments in the search for HIV cure should take into consideration the other uncharacterized reservoir sites of HIV-1 with a view to finding out how they respond to these novel agents.

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