Recent Insights into the HIV/AIDS Pandemic

Abstract

Etiology, transmission and protection: Transmission of HIV, the causative agent of AIDS, occurs predominantly through bodily fluids. Factors that significantly alter the risk of HIV transmission include male circumcision, condom use, high viral load, and the presence of other sexually transmitted diseases. Pathology/Symptomatology: HIV infects preferentially CD4⁺ T lymphocytes, and Monocytes. Because of their central role in regulating the immune response, depletion of CD4⁺ T cells renders the infected individual incapable of adequately responding to microorganisms otherwise inconsequential. Epidemiology, incidence and prevalence: New HIV infections affect predominantly young heterosexual women and homosexual men. While the mortality rates of AIDS related causes have decreased globally in recent years due to the use of highly active antiretroviral therapy (HAART) treatment, a vaccine remains an elusive goal. Treatment and curability: For those afflicted HIV infection remains a serious illness. Nonetheless, the use of advanced therapeutics have transformed a dire scenario into a chronic condition with near average life spans. When to apply those remedies appears to be as important as the remedies themselves. The high rate of HIV replication and the ability to generate variants are central to the viral survival strategy and major barriers to be overcome. Molecular mechanisms of infection: In this review, we assemble new details on the molecular events from the attachment of the virus, to the assembly and release of the viral progeny. Yet, much remains to be learned as understanding of the molecular mechanisms used in viral replication and the measures engaged in the evasion of immune surveillance will be important to develop effective interventions to address the global HIV pandemic.

Keywords: AIDS; HIV-1; antiretroviral therapy; epidemiology; pathology; treatment; virus entry.

Figure 1. FIGURE 1: Worldwide distribution of estimated HIV-1 infections in 2014, trends in the incidence of new infections from 2000 to 2014, and HIV-1 subtypes.

Numbers and percentages based on UNAIDS fact sheet 2015.

Figure 2. FIGURE 2: HIV-1 is a retrovirus that is approximately 90 - 120 nm in diameter and is enveloped by a host-derived plasma membrane.

Trimeric envelope glycoproteins gp120/41 form the spikes on the virions surface and are embedded in the membrane. The cytoplasmic tail of gp41 interacts with the HIV-1 matrix protein p17. During maturation the capsid protein, p24, makes up the cone-shaped core, which contains two positive-strand RNA copies of the HIV-1 genome, the reverse transcriptase protein, as well as a number of other important host proteins.

Figure 3. FIGURE 3: HIV-1 genome.

A schematic representation of the HIV-1 gene products encoded by the HIV-1 genomic sequence.

Figure 4. FIGURE 4: Different steps of the viral life cycle.

The infection cycle begins with the attachment of the envelope (Env) glycoprotein spikes with the CD4 receptor and the membrane-spanning coreceptor (step 1), leading to fusion of the viral and cellular membranes and entry of the viral particle into the cell (step 2). Partial uncoating (step 3) facilitates reverse transcription (step 4), which in turn yields the pre-integration complex (PIC). Following import into the cell nucleus (step 5), PIC-associated integrase orchestrates the formation of the integrated provirus (step 6). Proviral transcription (step 7) yields viral messenger RNAs (mRNAs) of different sizes. Following export (step 8), mRNAs serve as templates for protein production (step 9), and genome-length RNA is incorporated into viral particles with protein components (step 10). Viral-particle budding (step 11) and release (step 12) is accompanied or soon followed by protease-mediated maturation (step 13) to create an infectious viral particle.

Figure 5. FIGURE 5: The course of untreated HIV infection and changes after antiretroviral therapy.

In untreated HIV infection the blood CD4 T cell count progressively declines over the course of infection (A). After initiation of antiretroviral therapy the HIV RNA copy numbers significantly decrease below detection limit followed by recovery of CD4 T cells, which can vary notably between individuals (B). Adapted from .

Figure 6. FIGURE 6: Working model of HIV-1 entry.

HIV entry is initiated by attachment of gp120 to CD4, which induces a conformational change in gp120. Following engagement of coreceptor, gp120 undergoes further conformational changes that allow for the insertion of the gp41 fusion peptide into the host membrane. The formation of the six-helix bundle brings the host and viral membranes into close proximity and creates a fusion pore, allowing entry of the HIV capsid into the host cell. Adapted from .