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  In this article
   Introduction
   History
   Structure and Functi
   Structure and Fu...
   Transmission
   Pathogenesis
   A. Infection Of ...
   Be Infection of ...
   Life Cycle
   Activation
   Genetic Heteroge...
   A. Genomic Diver...
   B. HIV. Diversit...
   References

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REVIEW
Year : 1992  |  Volume : 58  |  Issue : 4  |  Page : 233-242

Human immunodeficiency virus




Correspondence Address:
Ritu Singh


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How to cite this article:
Singh R, Singh S, Kaur V. Human immunodeficiency virus. Indian J Dermatol Venereol Leprol 1992;58:233-42

How to cite this URL:
Singh R, Singh S, Kaur V. Human immunodeficiency virus. Indian J Dermatol Venereol Leprol [serial online] 1992 [cited 2019 Dec 11];58:233-42. Available from: http://www.ijdvl.com/text.asp?1992/58/4/233/3806



  Introduction Top


The story of human immunodeficiency virus (HIV) is perhaps the most exciting one in the medical sciences. It began in June 1981 when the Centers for Disease Control (CDC) reported 5 young. male homosexuals from Los Angeles having Pneumocystis carinii pneumonia. Since then Acquired Immunodeficiency Syndrome (AIDS) has spread like wildfire far and wide. The pace of scientific investigations has matched that of the epidemic. Perhaps no other virus has been studied so extensively in such a short time. Within 2 years of the detection of the disease the causative agent was identified, in the next year it was cultured and cloned. One more year, and we knew its nucleotide sequence. Here we summarize the salient features of HIV.


  History Top


HIV, the causative agent of AIDS, is a retrovirus. Retroviruses are RNA viruses possessing a specific enzyme known as RNA - dependent DNA polymerase or reverse transcriptase. [1] This enzyme has the capacity to reverse the ordinary flow of genetic information from DNA -- .> RNA to RNA ---> DNA. The family Retroviridae is divided into 3 subfamilies i.e. Oncovirinae, Spumavirinae, and Lentivirinae [1]. HIV belongs to the subfamily Lentivirinae. Lentiviruses cause slow infections in which there is a long period of latency before clinical features appear. HIV is the first lentiviral infection of man to be found and the only lentivirus to infect lymphocytes. [1]

Barre-Sinoussi et ate [2] detected retrovirus particles in a patient with lymphadenopathy in 1983 and named it lymphadenopathy-associated virus (LAV). Within a year the teams headed by Luc Montagnier of France [3] and Robert Gallo of the USA [4],[5] independently isolated and cultured the causative virus from AIDS patients. Gallo called the virus human T-­lymphotropic virus type III [4],[5] Levy et al, [6] who also isolated the virus in the same year, called it AIDS-related virus (ARV). Later all 3 viruses were found to be the variants of the same AIDS virus. [7] The controversy regarding the nomenclature of the virus was settled in 1986 when an international committee [8] named the causative agent of AIDS as HIV-1 and recommended that subsequent distinct isolates be called HIV-2, HIV-3, etc.

In 1986 a new lentivirus HIV-2, [9],[10]sub related but distinct from HIV-1, was identified in AIDS patients in West Africa. The clinical diseases caused by HIV-1 and HIV-2 are indistinguishable. The envelope glycoprotein gp 36 of HIV-2 is type specific. HIV-2 appears to have lesser virulence or penetrance than HIV-1. Nucleotide sequence analysis has revealed that HIV-2 has greater (70%) sequence homology with Simian Immunodeficiency Virus (SIV) than with HIV-1 (40%) pointing to a possible common ancestry.

HIV-1 is prevalent in the USA, Central Africa, Europe, and many other countries, while HIV-2 is largely confined to West Africa. Dual serological reactivity to HIV­1 and HIV-2 is a common occurrence in West Africa. A recent study [11] has indicated that mixed HIV-1/HIV-2 infections are common there and that infection by one HIV type does not prevent heterologous infection.

Some reports describing patients of acquired immunodeficiency without any evidence of HIV-1 or HIV-2 infection have appeared since 1989. [12],[13],[14] A recent editorial in the British Medical Journal [15] has discussed this situation and concludes that the claims of a new strain of HIV are premature. The complete understanding of the evolutionary divergence of HIV will have to await further studies.


  Structure and Function Top


Hockley et a! [16] and Gelderblom et at [17] have described the fine structure of HIV particles in detail. The diameter of HIV virion is approximately 110 nm. It is spherical in shape and contains an electron-dense core surrounded by a lipid envelope. The virus core contains 2 copies of 35S single-stranded genomic RNA and several proteins.

The envelope glycoprotein appears as spike-like projections on the virus, of which there are about 100 per virus particle. [18] Each physical spike contains four gp 160 molecules. [19] The gp 160 consists of an external portion (gp 120) and a transmembrane region (gp 41). The gp 120 binds with CD 4 receptor and gp 41 mediates fusion between viral envelope and target cell membrane. [20]


  Transmission Top


The virus has been isolated repeatedly from blood, semen, cerebrospinal fluid, cervical and vaginal secretions, breast milk, colostrum, urine, tears, and saliva of patients with AIDS and people at risk of developing AIDS .[21] sub HIV is known to survive in dried state for about 1 week and in liquid state for about 2 perhaps 3 weeks. [22] These data are based on laboratory experiments carried out using concentrations of HIV very much higher than those normally encountered in the patient's material. HIV can be transmitted through following 3 routes:

A. Venereal transmission of HIV can occur in homosexuals, bisexuals, and sex partners of risk group members. The virus spreads through genital secretions. [23] Transmission is more likely to occur during homosexual intercourse than during heterosexual intercourse. The risk of HIV transmission in one uncomplicated vaginal intercourse with an infected partner is estimated to be 1 in 500. [24] Presence of genital ulcers increases the risk of transmission. [25] Artificial insemination has also been reported to transmit HIV. [26]

B. Perinatal transmission of HIV can occur in children born to infected mothers. It is believed to occur transplacentally [27] and/or through breast milk. [28] If the mother has HIV infection the chances that the baby will get it are 20% to 50%. [29],[30]

A recent study has suggested that transmission of HIV-1 takes place either at the end of pregnancy or at delivery. [31] Another recent study [32] found higher rate of transmission of HIV-1 from mother to child with vaginal deliveries in which episiotomy, scalp electrodes, forceps, or vacuum extractors were used. This study suggested that caesarean deliveries may have a protective effect. Chances of HIV transmission by breast feeding are very low and do not outweigh the benefits of breast feeding. [33]

C. Parenteral transmission of HIV can occur in intravenous drug abusers (by sharing needles and syringes), haemophiliacs (who receive factor VIII concentrates), blood transfusion recipients, and health care workers. Transmission of HIV can occur by transfusion of whole blood, blood cellular components, plasma, and clotting factors. [34] Avoidance of donors from known risk groups and screening of donated blood for antibody against HIV has reduced the risk substantially, but the risk has not been eliminated because of the following 2 reasons. First, the antibody test for HIV-1 is not foolproof. False­ negative results, although very infrequent, do occur. The sensitivity and specificity of ELISA kits evaluated in the USA and Europe were found to be in the range of 95% to 99.9%. [35]Second, antibodies may take 3 to 17 weeks to develop after infection. Therefore, the blood donated after infection but before seroconversion would pass undetected. [36],[37] This period between infection and seroconversion is known as window period. Health care workers can be infected by HIV during needlestick injuries. However, the risk of transmission in one such exposure is only about 0.5%. [38]

A recent study provided no evidence that HIV could be transmitted by insect bites. [39]


  Pathogenesis Top


HIV is a cytopathic retrovirus. [40] It has a tropism for cells expressing CD 4 molecules on their surface . [41],[42] The infection of HIV involves interaction between gp 120 and CD 4 molecule as indicated by their coprecipitation by antibodies directed against either ' of the proteins . [43] The definitive proof that CD 4 molecule is the high affinity receptor for HIV came from the experiment in which CD4 -cell (such as HeLa) became infectable by transfection of a cloned CD 4 gene. [44] In addition to helper T-cells, other cells such as monocytes and macrophages, Langerhans cells, follicular dendritic cells, glial cells, and certain colon tumour cell lines are also susceptible to HIV infection [45],[46],[47] These cells express low levels of CD 4 molecules on their surface. It appears that the expression of CD 4 is not necessary to confer infectivity and that there may be an alternative receptor which remains to be determined.


  A. Infection Of Lymphoid System Top


One of the pathological consequences of HIV infection is a dramatic depletion of CD4 +T-cells, even if relatively few cells are actually infected. [48] This loss of CD4+ cells affects functions of other cells of immune system also, directly or indirectly, leading to the development of immunodeficiency. Several possible mechanisms have been suggested to explain the cytopathic effect (CPE) of HIV:

(i) CD4 - gp 120 interaction itself may induce cell death.[40],[49]

(ii) Syncytia formation may be another possibility. It involves fusion of infected cells expressing viral glycoproteins (gp 120, gp 41) on their surface with uninfected cells expressing CD4 molecules. [42] The syncytia are unstable in culture, do not proliferate and die within 48 hours. [50] However, there is little evidence that this process occurs in vivo. [1]

(iii) Profuse virus budding or complexing of CD4 and gp 120 may impair the permeability of cell membrane and cause cell death. [51]

(iv) CD4 + cells may be killed by autoimmune phenomena. Extracellular gp 120 (shed by infected cells) may bind to CD4 expressed on the surface of uninfected T-cells. This may lead to antibody-dependent cell-mediated cytotoxicity against such cells. [52] Also, autoimmune reactions may occur against infected lymphocytes that express gp 120 on the surface. The possibility that HIV might mimic MHC II and the normal immune response to the virus could represent an autoimmune process similar to graft-versus-host disease has been recently suggested. [53]

(v) Accumulation of large amount of unintegrated viral DNA in the infected cells can be an important factor in HIV-induced CPE. [54]

(vi) Apart from the above mechanisms which attempt to explain-the death of mature CD4 + cells, another possibility has been suggested. [55] CD4 + T-cell precursors (expected to occur in low frequency) may be infected with HIV resulting in impaired production of mature CD4 +cells.

We do not fully understand how HIV causes the damage it so clearly wreaks. [56] This inability to explain the profound CD4 + T-cell depletion in AIDS patients led Duesberg [57] to suggest that AIDS and HIV are correlated and that HIV is not the direct cause of AIDS. He emphasized that HIV displayed only weak CPE and that the viral load was generally much too low to account directly for the remorseless destruction of CD4 + lymphocytes characteristic of the disease. Duesberg's view has been countered forcibly [56],[58]sub and has not gained favour.

In addition to quantitative depletion of CD4 + cells, these cells are functionally abnormal as well in AIDS patients. [59] This occurs in early course of infection prior to the dramatic depletion of CD4 + cells. The cell is unable to respond to antigens even if presented by normal HLA compatible antigen-presenting cells.

It has been shown that monocytes and macrophages harbour HIV in vivo [46] and are likely to play an important role in the pathogenesis. [60] Since these cells are relatively refractory to the CPE of HIV, they may act as major reservoir of HIV in the body and may disseminate the virus to various organs in the body.


  Be Infection of Central Nervous System Top


In addition to lymphoid system, the nervous system is a major target of HIV infection. Monocytes appear to be the predominant cell type infected by HIV within the central nervous system (CNS) of infected individuals. [61] Following mechanisms have been suggested to explain HIV-induced CNS injury and dysfunction.

(i) In brain monocytes are somehow activated to release cytokines that are either directly toxic to neurons or recruit other tissue-damaging inflammatory cells. [55]

(ii) Direct infection of endothelial _cells by HIV has been reported [62] which may alter the permeability of small vessels and consequently disrupt the blood-brain barrier.

(iii) The viral glycoprotein (gp 120 ) can inhibit the growth of neurons in the presence of neuroleukin. [63]


  Life Cycle Top


The first step in the initiation of infection is binding of a virus envelope glycoprotein (gp 120 ) to a specific receptor (CD4) on the surface on the target cell. The mode of entry of enveloped viruses is of 2 types. First, a pH-dependent process which causes internalization of virus into endosomes by receptor-mediated endocytosis.

Second, a pH-independent process which involves direct fusion of the virus envelope with the plasma membrane of target cell. The exact steps that follow the binding of gp 120 and CD4 in case of HIV are not clear. Electron microscopy and other experiments have suggested that HIV uses second mode of entry [64] and that receptor- mediated endocytosis is not required for HIV entry. Whatever be the mode of entry of HIV, it is possible that truncated CD4 molecules are also internalized in response to HIV binding.

Once internalized, the viral RNA is transcribed into double-stranded proviral DNA by reverse transcriptase. All reverse transcriptases (RTs) lack proofreading function. HIV RT seems to be significantly more error- prone. than other RTs, with frequency of misincorporation ranging from 1:1700 to 1:4000. [65],[66] This is partly responsible for high mutation rate of HIV seen in vivo. This proviral DNA then migrates to the nucleus where it maneuvers to establish itself within the host cell DNA.

Like other retroviruses, HIV also requires activation of T-cells for productive infection. [67] In resting T-cells infection is stable but nonproductive. [67] The onset of productive infection leading to disease is dependent on mitogenic or antigenic stimulation of resting T-cells (see "Activation"). However, the requirement of host cell proliferation for productive infection is not universal. There are exceptions such as nondividing cultures of monocytes and macrophages can be productively infected by HIV.

The proviral DNA is transcribed to form genomic RNA and m RNA. In addition to typical retroviral genes, gag, pol and env, HIV encodes at least 8 other genes such as tat, rev, nef, vif,vpr, vpu and tev/ tnv. The regulation of gene expression has been well described by Cann et a1. [68] Translation of viral m RNA results in the formation of HIV proteins which then assemble to form mature virus particles. Release of mature virus particles from the cell surface occurs by an active process of exocytosis. [1]


  Activation Top


Several factors have been implicated to play a role in the outcome of HIV infection, which ranges from asymptomatic carrier state to full-blown AIDS, as well as from latency to reactivation. Among the viruses which commonly cause infections in AIDS patients, [69] Herpesviruses, Papovaviruses, Humanherpes-viruses-6, Adenoviruses, and HTLV-1 can transactivate HIV-1 LTR. Other viruses which help in activation of HIV are Cytornegaloviruses, Epstein-Barr viruses and Hepatitis B viruses. These viruses contribute to AIDS progression by transcriptional activation or reactivation of HIV as well as through additional mechanisms. The activation may also be triggered by stimulation of host cell cytokines. [68]


  Genetic Heterogeneity Top


All isolates of HIV do not represent the same genetic entity. HIV exhibits a remarkable degree of diversity in the genome. [70] The list of genetic sequences of HIV-1 continues to grow incessantly. [71],[72]

Even in a single epidemiological context, isolates of virus from different patients show considerable variation one from another and the differences are even greater when isolates from different geographical regions are compared. Moreover, striking genetic and antigenic variation in env has been observed in viruses isolated sequentially from individual subjects during the course of infection; and, even worse, there is evidence that viruses isolated from different tissues of a given host may differ in biological and molecular properties. [18] Therefore, to study the divergence of these viruses one can assess the extent of variation among viruses obtained from single patient and among viruses obtained from different patients. This type of study may give some interesting insights into the various factors that participate in the generation of genetic variants.


  A. Genomic Diversity In A Single Infection Top


Restriction enzyme mapping [73] of multiple virus clones has shown that the clones obtained from a single individual are related to each other. They can be distinguished only on the basis of their unique set of restriction enzyme sites.

Highly related HIV genomes obtained from the same patients can have very different biological properties with respect to replication efficiency, tropism, and susceptibility to virus neutralization. [74] The genomic composition of HIV isolate determines its predominant biological phenotype. Selective pressure in the infected host may change this composition. Thus differences in sequentially obtained isolates [75] could be due to selection from an existing population rather than change over time.

Selective pressure is one consideration to explain viral evolution. Another is mutation due to error-prone function of RT [65],[66] The extent of mutation is dependent on error frequency of RT and the number of replication cycles in a given time. Another phenomena which can contribute to the origin of diversity may be the recombination among existing genotypes.


  B. HIV. Diversity In Population Top


The degree of similarity among any 2 HIV isolates from a population is in general less than that among viruses from the same person. Therefore, the viruses derived from donor-recipient pairs will show little divergence while viruses from same cohorts and same geographical areas would have less heterogeneity than those from a distant population. The extent of divergence increases with the length of time the virus has been in a given population. In 1988 Smith et a [76] attempted to calculate the time of entry of HIV into man based on the genetic distance between isolates having a known time of divergence. The most divergent part of the genome is the envelope gene. [77]

AIDS research is proceeding at a frantic, almost dizzying pace. Despite all its wiles, the HIV can not be long on the loose, surrounded as it is by an army .of investigators in hot pursuit. [55]

 
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