Long Term Non-Progressor or LTNP in HIV Infection are cases where infected individuals maintain high CD+ and CD8+ T- cell counts and remain asymptomatic.
Types of Progressor in HIV Infected Individuals
HIV infected individuals have a variable rate of progression to AIDS. Based on that, progression can be divided into three types:
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Rapid Progression: Upon infection by HIV, the development of AIDS occurs within three years.
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Intermediate Progression: Development of AIDS in infected individuals after seroconversion occurs slowly between periods of 3 to 10 years.
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Long Term Non-Progression: These are HIV infected individuals whose CD+ and CD8+ T- cell counts are record high and remain asymptomatic of an AIDS-related disease. This type of progression comprises 5% of the total HIV infected individuals.
Fast track>> Seroconversion: The transition in an individual from infection with HIV to the detectable presence of HIV antibodies in the blood.
What is HIV? Human immunodeficiency virus (HIV) is a retrovirus. Its pathogenesis is multi-factorial and infects T-cells through high-affinity interaction between the virion envelop glycoprotein (gp120) and the CD4 molecule. Thereby it causes acquired immunodeficiency syndrome (AIDS). The virus invades various cells of our body's immune system such as CD4+ T cells and monocytes, causing a decline in the CD4+ T cell numbers. These numbers then go below the critical level leading to loss of cell-mediated immunity, which renders the body more susceptible to opportunistic infections, cancer, and other diseases. How does HIV Invade the Cells of our Immune System? Once the glycoprotein (gp120) of the virion envelop binds to the CD4 on the T cells, the following action occurs: First, the nucleocapsids containing the viral RNA genome and enzymes enter the target cells of the body and released their genetic materials and necessary enzymes. Once released, this genetic material, and enzymes from the core protein, the viral reverse transcriptase catalyzes the reverse transcription of single-stranded RNA (ssRNA) to form a duplex of RNA-DNA hybrids. This is followed by the formation of double-stranded DNA (dsDNA) from an RNA template, which requires partial degradation by the enzyme ribonuclease H. The dsDNA is translocated into the host cell nucleus and integrated into the genome by the help of enzyme integrase. In the nucleus, proviral DNA is transcribed into genomic ssRNA by the transcription factors and is exported into the cytoplasm where the host cell ribosomes catalyze the synthesis of viral precursor proteins. Upon cleavage of the precursor protein by viral protease enzyme, the viral genome ssRNA and proteins are assembled beneath the host cell plasma membrane forming virion buds from it. During maturation, either in the forming buds or budding off from the host cell, the HIV protease cleaves the viral poly-protein into individual functionally active HIV proteins. Finally, the mature virions are ready to infect other host cells.
Failure of the Cells to Counter HIV Infection
Several reasons are reported for the failure of the immune system to cope with HIV infection and preventing the development of AIDS. Infection by HIV in humans reduces the CD4+ T cells in the gut mucosal level, which has a direct consequence of the cytopathic infection of the target cells. The compromised function of gastro-intestinal mucosa may result in the discharge of microbial products from the gut to the circulation and contributing to chronic activation and exhaustion of the immune system.
HIV can also develop a latent infection in CD4+ T cells and persist undetected to CD8+ T cells, and doing so; the replication can perform later upon infection and generate new virions. The antigenic mutation within the T cell epitopes can affect the binding capacity of major histocompatibility complex (MHC) molecules to the viral peptides, resulting in the inability of the T cell receptors to recognize the MHC-peptide complex.
Also, the unique lymphotropic nature of HIV-1 strain, in addition to its ability to infect immune cells, favors its interaction with the surface molecules. These molecules later signal through their normal transduction pathway, exerting a direct effect on leucocytes without productively infecting them.
Long Term Non-Progressors (LTNP) in HIV
LTNP is a term characteristic of HIV infected individuals whose CD4+ and CD8+ T-cell count is stable over time and greater than 600 cells/µl, having low levels of HIV virus in the peripheral blood, and no symptoms of HIV evoked disease.
With the introduction of techniques for measuring viral load, it has come to light that some of these HIV infected patients had low or non-detectable viral replication even prior to the introduction of combination anti-retroviral therapy (cART) and did not progress to AIDS. Based on the viral load, LTNP can be further divided into two groups:
- Long Term Non-Progressors: Individuals belonging to this group have low detectable plasma viraemia (< 5000 HIV-RNA copies/ml).
- Elite or Natural Controllers: Individuals who show plasma HIV-RNA values persistently below 50 copies/ ml. Such a non-progressor phenotype is known as controllers due to their ability to control viral replication in the absence of cART.
Controllers have a preserved CD4+ cell production with a bone marrow function, a thymic output, a lymphopoiesis, and an interleukine balance (IL7/IL7-R) resembling non-infected individuals.
Fast track: Viraemia>> The presence of a virus in the bloodstream.
Various Metabolism and Their Roles in LTNP in HIV
Several research findings have claimed that the cellular metabolism of the host and virus plays a vital role in long term non-progression.
The Host Factor
Cholesterol Metabolism
Whilst the genetic basis is still unexplored; there are reports that the cholesterol level in immune cells may have a decisive influence on HIV spread within the body. Cholesterol and lipid raft plays a significant role in membrane fluidity, and at the same time, viral assembly occurs on the cholesterol-rich lipid rafts of the plasma membrane. Cholesterol depletion from the virus-producing cells has been shown to suppress virus production, whereas the same chromosome depletion from mature virions or target cells inhibits virus-cell fusion and infection.
ATP-binding cassette A1 (ABCA1), a cellular cholesterol transporter, decreases the cholesterol level and affects the ability of antigen-presenting cells (APCs) – dendritic cells (DC) and B cells in enabling trans infection. This inability of APCs is said to be an innate property of non-progression. That, the low cholesterol level makes the DCs and B cells unable to capture HIV and its transfer to susceptible cells, which requires a tight contact between cells to form a virological synapse.
Changes in the plasma membrane fluidity due to altered cholesterol and sphingolipid compositions can alter the expression and function of CD4 and CCR5 and HIV cis infection.
Fast track>> Trans-infection: A process by which APCs (DCs and B cells) take up HIV and participate in enabling the infection of CD4+ T cells.
HIV-Specific CD4+ and CD8+ T Cell Response
The mechanism of how CD4+ cells are not depleted but actively participate in maintaining an effective antiviral immunity is still unknown. In individuals whose immune system controls viremia, it is reported that CD4+ T cells produce interferon (IFN)-γ and antiviral β-chemokines, including RANTES, and the macrophage inflammatory proteins (MIP-1α and MIP-1β).
It is also possible that the contribution of anti-HIV CD8+ T cells response could play a significant role in controlling the progression of AIDS. During the primary infection, a vigorous HIV-specific CD8+ T cell immune response was detected.
A highly active cytotoxic T lymphocyte (CTL) response in terms of both CD8 effector function and the number of epitopes recognized may be capable of controlling HIV replication in LNTP. This lead to an equilibrium between CTL response and HIV load, and thus maintain a stable CD4+ T cell number over time.
The Virus Factor
Nef protein of HIV plays a major role in viral replication and infection. LTNPs and slow progressors (SPs) derived Nef proteins are defective or are less capable of enhancing viral replication and/or infectivity.
Nef activates the transcription of sterol-responsive element-binding factor 2 (SREBF-2) and regulator genes of SREBF-2, thereby inducing cholesterol uptake and biosynthesis. Nef reduces cholesterol efflux from the cells by inhibiting the ATP-binding cassette A1 (ABCA1), a cellular cholesterol transporter.
Not only this, but Nef also increases the intracellular cholesterol content as they bind cholesterol and deliver it to the lipid rafts. This leads to an increase in viral fecundity and pathogenicity.
Additional to the above role played by the host and virus cell’s metabolism in delaying the progression to HIV, several other factors also aid in LTNP. Individual or synergetic effect of serum factors (neopterin and beta 2-microglobulin) with CD4+ T-cells; heterozygosity at class I loci (HLA-A, HLA-B, and HLA-C); the function of thymus – a lymphoid organ; the presence of polymorphism in co-receptors (CCR5-delta32), etc., are reported to take part in resisting against the progression of HIV infection to AIDS.
Image Credits:
Featured Image: Long Term Non-Progressor in HIV Infection
HIV-1 interaction with CD4 receptor of a Th human lymphocyte
Ph.D. Biotechnology, Manipur India
