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Categories of people in relation to HIV-1 disease
- "Normal" HIV-1
infected persons Highly variable disease progression rates between individuals are well-recognized, with progression categorized as rapid, typical or intermediate and late or long-term non-progression. The majority of infected individuals (70–80%) experience intermediate disease progression in which they develop AIDS-related illnesses within 6–10 years of acquiring HIV. Ten to 15% are rapid progressors who have a fast CD4+ T-cell decline and occurrence of AIDS-related events within a few years after infection. The late progressors (5%), can remain healthy without significant changes in CD4 count or HIV-RNA for over 10 years. This wide variation in speed of disease progression depends on combination of immunological and virological factors, host genetics and other host factors (age, weight, psychological factors, health status).
Immunological factors: T-lymphocytes' (CD4+ and CD8+) count and function and immune activation (immune-activation-driven apoptosis of CD4+ cells, more than a direct virological pathogenic effect, is responsible for the decline in CD4+).
Virological factors are viral load at set point, resistance mutations, chemokine receptor tropism, and viral subtype and race.
individuals (ESN) ESN is someone who is not HIV-infected despite a history of multiple unprotected sexual episodes (with an HIV-seropositive partner) for 4 years or longer, with at least eight episodes of at-risk intercourse within the 4 months before study entry and an average of 30 reported unprotected sexual contacts per year. Individuals homozygous for the D32 allelic variant of the CCR5 protein, the co-receptor for the macrophago-tropic R5-HIV viruses, display a strong protection to sexually transmitted HIV infection. However, protection is not absolute and some rare cases of HIV-1 infection despite this genotype have been reported. These patients harboured CXCR4-using viruses, suggesting that CXCR4 was the co-receptor responsible for initiating infection. The CCR5 D32 allele occurs with a frequency of 4–15% in Caucasian ethnicity (even higher frequencies can be observed in Northern Europeans) and homozygous individuals are overrepresented in ESN. The CCR5 D32 variant is nevertheless completely absent in sub-Saharian African populations, where the majority of HIV infection occurs and where many investigators have described numerous cohorts of ESN.
non progressors A small minority (<2%) of HIV-seropositive patients characterized by a long course infection that does not result in signs or symptoms of AIDS, despite the absence of antiretroviral therapy. CD4 T cell counts are stable and HIV plasma viremia is low in LTNP. LTNPs form a very heterogeneous population. Indeed, these patients, being only defined on an immunological basis (CD4+ count), have highly variable viral loads, and up to 90% of individuals included in LTNP cohorts eventually had a decline in their CD4+ T cell counts and progress to AIDS.
- "Classical" LTNP Show variable and low but detectable viral load (<5000 HIV-RNA copies/ml), maintain healthy CD4+ cell counts for 20 years and more; eventually may progress to AIDS.
- Elite controllers Characterized by a consistently undetectable plasma viremia (<50 copies/ml). Also called HIV controllers (HICs), they are also known as elite controllers, elite suppressors, or elite nonprogressors. HICs appear to represent less than 1% of all HIV-infected patients. All HICs are fully HIV seropositive and have very low and stable amounts of viral DNA in their peripheral blood mononuclear cells (PBMC). An effective, multifunctional HIV-specific CD8+ T-cell response is thought to be central to viral control in these individuals.
Lately, the International HIV Controller Consortium has somewhat relaxed the requirements
that define this population of HIV-infected individuals. Thus, by the new definition,
elite controllers are HIV-infected patients with HIV RNA levels below 50 copies/ml) despite
the absence of antiretroviral therapy (for at least 1 year at the time
of the study). Spikes of viremia up to 1000 copies/ml) are accepted in elite controllers,
as long as these episodes are not consecutive and represent the minority of all
A temporary increase in VL in someone who previously had undetectable virus and who later returns to having undetectable virus is called blip. The viral load during a blip is usually low (50 to 500 copies/mL).
It is actually impossible to predict whether the resistance to disease progression shown by LTNP and elite controllers will last indefinitely or whether progression to AIDS will eventually be detected in these patients.
Mechanisms that help to maintain undetectable plasma viral loads
Non-cytotoxic, non-major histocompatability complex (MHC)-restricted antiviral activityThis activity is mediated by soluble factors such as cytidine deaminases (e.g. APOBEC3G), which induce lethal hypermutations of the viral genome, Fv1/TRIM5α proteins, which restrict the incoming retroviral capsid, and tetherin, which impedes the release of nascent HIV virions from the cell surface. Recent analyses have shown that these host factors all evolved under positive selective pressure due to past encounters with ancient viruses.
An HLA-class I-restricted cytotoxic T lymphocyte (CTL) responseHuman leukocyte antigen (HLA) (also known as major histocompatibility complex (MHC)) genes are highly polymorphic loci encoding for cellular surface molecules that are responsible for antigen presentation to T lymphocytes. The efficiency of this process differs amongst individuals because of the high number of allelic variants of HLA class I (A, B and C) and HLA class II genes (DR, DQ and DP). The HLA class I genes encode molecules that bind antigens derived from the processing of intracellular pathogens and present these antigens to cytotoxic T lymphocytes (CTL). In contrast, HLA class II genes produce molecules that bind peptides of extracellular origin and present them to CD4+ T helper lymphocytes. Individuals expressing the most polymorphic HLA variants and those variants with the best ability to bind to exogenous peptides, mount a more vigorous immune response against pathogens. Many studies report solid, confirmed associations between HLA molecules and different patterns of HIV disease. Most notably, HLA-B*57 and HLA-B*27 have been associated with long-term survival. Both of these class I molecules restrict CTL responses by presenting peptides selected from highly conserved regions of Gag. Mutations that allow escape from these CTL-specific responses arise only at great cost to viral fitness which is translated into higher genetic diversity of viral quasispecies, lower viral loads, and greater survival benefits. However, less than 50% of elite controllers show the presence of HLA-B*57 and an even smaller percentage (20%) express HLA-B*27.
Characteristics of CD8+ T cells from elite controllers
- The ability to generate a multifunctional response after stimulation with their cognate antigen that includes degranulation (releases antimicrobial cytotoxic molecules from secretory vesicles called granules) and chemokine and cytokine secretion (including IL-2).
- The ability to proliferate upon antigenic stimulation (progressors' lack of CD8+ T cell proliferation in response to HIV antigen stimulation reflects the impaired function of these cells).
Comparison of HIV-1 patients' immunological profiles
|progressors -HAART||high CD38 and HLA-DR expression (chronically activated)||PD-1 high (leads to apoptosis and death)|
|progressors +HAART||low CD38 and HLA-DR expression (not activated)||PD-1 low|
|elite controller||low CD38 (not activated) and high HLA-DR expression (a high capacity for expansion)||PD-1 low|
The activation phenotype of HIV-specific CD8+ T cells with their discordant phenotype in HICs is unusual. This phenotype might indicate optimal activation associated with efficient antiviral activity, whereas high CD38 expression in progressors could be due to high viral load and be driven by cytokines. This deleterious activation status can lead to PD-1 expression, inefficiency, senescence, and, ultimately, apoptosis. By contrast, PD-1 expression by HIV-specific CD8+ T cells is low in HICs.
Immunity Immune protection provided by the direct action of immune cells such as CD8 cells, macrophages, and other white blood cells, rather than by antibodies.
- Humoral Immunity Antibody-based immune response. Immune cells called B-cells produce antibodies against foreign invaders.
- Chemokines Proteins that serve as chemical messengers to control the activities of the immune system.
- Cytokine A protein produced by leukocyte (white blood cell) that acts like a chemical messenger between cells. Cytokines are essential for a coordinated immune response. Cytokines include interleukines (examples: IL-2, IL-7) and interferons (INF).
- HLA-DR A major histocompatibility complex, MHC class II, cell surface receptor encoded by the human leukocyte antigen complex on chromosome 6 region 6p21.31.
differentiation 38) Also known as cyclic ADP ribose hydrolase. A glycoprotein found on the surface of many immune cells (white blood cells), including CD4+, CD8+, B and natural killer cells. CD38 also functions in cell adhesion, signal transduction and calcium signaling. The CD38 protein is a marker of cell activation.
differentiation 4) A glycoprotein expressed on the surface of T helper cells, regulatory T cells, monocytes, macrophages, and dendritic cells.
- CD4+ cell Also known as helper T cell or CD4+ lymphocyte. A type of infection-fighting white blood cell that carries the CD4 receptor on its surface. By providing help to B cells and CD8+ T cells, CD4+ T cells play an important role in the humoral and cytotoxic response to pathogens. They also play a key role in down modulating immune responses thereby preventing chronic inflammation. Chronic activation of CD4+ cells as a result of HIV infection is one of the main reasons of their death. The loss of CD4+ T cells leads to the collapse of the immune response in patients with progressive disease.
- CD8+ Cell Also called a cytotoxic T lymphocyte (CTL) or killer cell, or suppressor cell. A type of white blood cell that is able to identify and kill cells infected with bacteria, viruses, or foreign invaders.
- Macrophage A relatively long-lived phagocytic cell involved in antigen presentation and other immune surveillance functions in mammalian tissues.
- PD-1 Programmed Death 1, a Type I membrane protein of 268 amino acids. PD-1 is a member of the extended CD28/CTLA-4 family of T cell regulators.
- "HIV Long-Term Survivors"[Mesh] in PubMed
Taborda-Vanegas N, Zapata W, Rugeles MT. Genetic and Immunological Factors Involved in Natural Resistance to HIV-1 Infection. Open Virol J. 2011;5:35-43.
- Target cells have polymorphisms in CCR5 gene or other alternative viral coreceptors, such as CCR2 (1), all of them induce low or non-expression of these coreceptors, inhibiting viral entry.
- This step can be also blocked by high production of the coreceptors ligands, MIP-1α/β, RANTES and SDF-1 (2).
- Elevated spontaneous and inducible apoptosis of monocytes and other HIV-1-target cells has been reported in ESNs (3).
- Increased release of soluble antiviral factors APOBEC3G, CAF, α and β- defensins, type I IFN, LIF, MIP-1α/β, RANTES, RNases, SDF-1, SLPI, TRIM5α and elafin block viral entry or replication (4).
- ESNs individuals exhibit high activity in NK cells and DCs. NK cells express KIR3DS1 and KIR3DL1 related to cell activation (5)
- and are able to produce IFN-γ (6). DCs also produce IFN-α (6).
- and express the co-stimulatory molecules CD80 and CD86 (7)
- Type I IFN induces HLA expression, apoptosis of infected cells, production of antiviral molecules, and block viral replication. The specific immune response is characterized by the presence of CTLs restricted to HLA-B57 and –B27, presenting immunodominant peptides (8),
- production of cytokines such as RANTES, MIP-1β, IL-6, IFN-γ, TNF-α and β and IL-2 that increase the immune response and expression of markers associated with T cell activation (9).
- B-cells produce neutralizing IgA antibodies, detectable in serum, mucosa and breast milk (10).
Strebel K, Luban J, Jeang KT. Human cellular restriction factors that target HIV-1 replication. BMC Med. 2009 Sep 16;7:48.
Recent findings have highlighted roles played by innate cellular factors in restricting intracellular viral replication. In this review, authors discuss in brief the activities of apolipoprotein B mRNA-editing enzyme 3G (APOBEC3G), bone marrow stromal cell antigen 2 (BST-2), cyclophilin A, tripartite motif protein 5 alpha (Trim5α), and cellular microRNAs as examples of host restriction factors that target HIV-1.