In 1981, the Centres for Disease Control reported cases of Pneumocystis carinii pneumonia and Kaposi's sarcoma in previously healthy young male homosexuals. Before then, pneumocystis carinii was mainly known to occur in immunodepressed patients following organ transplantation or suffering from congenital immunodeficiencies. Shortly afterwards, the same condition was seen in IV drug abusers, haemophilliacs and babies of IV drug abusing mothers. It was recognized that these patients had profound immunosuppression due to the depletion of T4 helper lymphocytes. The name acquired immunodeficiency was coined for this syndrome. Epidemiological studies soon established that this disease was infectious, transmitted by sexual intercourse, blood or blood products. There were initial difficulties in isolating the virus due to the fact that the lymphocytes of patients died early. Eventually the virus was isolated by Montagnier and Gallo in 1984. In 1986, HIV-2 was isolated from West Africa which did not cross-react serologically with HIV-1 in screening tests.
Belong to the lentivirus subfamily of the retroviridae
Enveloped RNA virus, 120nm in diameter, contains 2 copies of the RNA genome
Replication depends on reverse transcriptase
cytopathic viruses, in contrast to the oncornaviruses
HIV-2 less cytopathic for in cell culture than HIV-1, and shares 40% nucleotide homology with HIV-1
HIV-II is more related to SIV than to HIV-I
genome consists of 9200 nucleotides (HIV-1)
gag core proteins - p15, p17 and p24
pol - p16 (protease), p31 (integrase/endonuclease)
env - gp160 (gp120:outer membrane part, gp41:transmembrane part)
other regulatory genes are present in addition to the above ie. tat, rev, vif, nef, vpr and vpu
Electronmicrograph of HIV particles
Schematic representation of an HIV particle
The replication cycle is as follows; The first step of infection is the binding of gp120 to the CD4 receptor of the cell, which is followed by the fusion of the virus and cell membrane and is mediated by the gp41 molecule. The virus then penetrates into the cell and uncoating, reverse transcription, provirus synthesis and integration takes place. This is followed by the synthesis and maturation of virus progeny.
Source: Mims C, Playfair J, Roitt I, Wakelin D, Williams R. 1993.
Medical Microbiology. p. 24.16
During 1996, members of the seven-transmembrane spanning receptor family of chemokine receptors were proved to be the necessary co-receptors for HIV-1 entry. These receptors were CXCR4 (fusin) for T-cell line (T)-tropic strains and (principally) CCR5 for macrophage (M)-tropic strains. It is important to note that both M- and T-tropic viruses replicate in primary CD4-positive T cells (Figure 1), despite the confusing nomenclature, which will soon be revised.
The profound immunosuppression seen in AIDS is due to the depletion of T4 helper lymphocytes. In the immediate period following exposure, HIV is present at a high level in the blood (as detected by HIV Antigen and HIV-RNA assays). It then settles down to a certain low level (set-point) during the incubation period. During the incubation period, there is a massive turnover of CD4 cells, whereby CD4 cells killed by HIV are replaced efficiently. Eventually, the immune system succumbs and AIDS develop when killed CD4 cells can no longer be replaced (witnessed by high HIV-RNA, HIV-Antigen, and low CD4 counts).
HIV-1 Half-Lives. Activated cells that become infected with HIV produce virus immediately and die within one to two days. Production of virus by short-lived, activated cells accounts for the vast majority of virus present in the plasma. The time required to complete a single HIV life-cycle is approximately 1.5 days. Resting cells that become infected produce virus only after immune stimulation; these cells have a half-life of at least 5-6 months. Some cells are infected with defective virus that cannot complete the virus life-cycle. Such cells are very long lived, and have an estimated half-life of approximately three to six months.
The natural course of HIV infection is as follows;
1. Seroconversion illness - this is seen in 10% of individuals a few weeks after inoculation and coincides with seroconversion. These patients present with a mononucleosis like illness which comprises of fever, sore throat, enlarged lymph nodes, skin rash, joint aches and general malaise.
2. Incubation period - this is the period when the patient is completely asymptomatic and may vary from a few months to a more than 10 years. The median incubation period is 8-10 years. Children tend to have a shorter incubation period.
3. AIDS-related complex or persistent generalized lymphadenopathy - at the end of the incubation period, a number of signs and symptoms may appear which do not fulfill the definition of AIDS or other HIV-associated syndromes. These include slight immunological, dermatological, haematological and neurological signs. Constitutional symptoms, such as fever, weight loss, night sweats, and diarrhoea may develop. Generalized lymphadenopathy may be seen. Laboratory findings may show a decrease in the CD4 count, hyperimmunoglobulinaemia and cytopenias.
The lymphadenopathy syndrome is defined as the enlargement of lymph nodes to 1 cm or more at 2 or more body regions which persists for more than 3 months without any other recognizable cause other than HIV infection. AIDS-related complex is defined as fever, weight loss, night sweats, or chronic diarrhoea of more than 1 month's duration in the presence of disturbances of CMI and in the absence of any other recognizable cause other than HIV infection. These definitions may be in part overlapping and are not mutually exclusive and they can be described generally as pre-AIDS.
4. AIDS - The first manifestation of HIV infection may be noted at any disease stage and the different stages may not occur consecutively. The transition to full-blown AIDS may occur rapidly or slowly. The disease progression is probably influenced by cofactors, such as other virus infections, stress, genetic makeup of the individual etc. Poor prognostic factors include the serial decrease in the number of CD4 lymphocytes, the reappearance of HIV antigen in the blood, the decline or disappearance of anti-core antibodies, and increased levels of B2-microglobulin and neopterin. The diagnosis of AIDS is established with the appearance of opportunistic infections, or of certain neoplasms, such as Kaposi's sarcoma, primary lymphoma of the brain and other non- Hodgkin's lymphomas. In the US, the diagnosis of AIDS is also established by the finding of a CD4 count of less than 200 cells/mm3.
pneumocystis cariniI (now thought to be a fungi)
toxoplasmosis of the brain
crytosporidosis with diarrhoea
candidiasis (oesophagus, trachea, lungs)
crytococcosis, extrapulmonary histoplasmosis
Mycobacterium avium complex
atypical mycobacterial disease
multiple or recurrent pyogenic bacterial infection
Opportunistic infections by protozoa, fungi, bacteria and viruses are seen in patients with aids. Pneumonia caused by Pneumocystis carinii is the most frequent opportunistic infection in AIDS patients in N. America and Western Europe. The typical symptoms are shortness of breath on exertion, dry cough and fever. Diagnosis requires bronchoscopy and the demonstration of Pneumocystis in the lavage fluid. Pentamidine and co-trimoxazol are the treatment of choice. Toxoplasmosis is particularly relevant because it causes CNS disease. It can be treated by a combination of pyrimethamine and a sulfonamide. Cryptosporidium frequently causes intractable diarrhoea for which no therapy is available.
Candida Albicans is the second most frequent opportunistic infection in AIDS patients. Thrush of the oral cavity is frequently seen in patients with pre-AIDS. Candidiasis of the oesophagus is a CDC criterion defining AIDS. Therapy is relatively simple with amphomoronal solution or ketaconazol tablets. Of further clinical importance is infection with the fungus crptococcus neoformans which, if untreated, is fatal in all cases. Early diagnosis may be made by the demonstration of the fungus or fungal antigen in the CSF.
An increasing problem are infections with mycobacteria. In N. America and Western Europe infections with the atypical mycobacteria, M. avium-intracellulare and M. Kansaii etc. dominate. In the developing countries, particularly in Central Africa, the classic M tuberculosis is more frequent. Although classic TB is treatable, no therapy exists for atypical mycobacteriosis.The most frequent viral infections are caused by CMV, HSV and VZV. CMV causes retinitis, colitis, or less frequently pneumonitis and hepatitis. Treatment is possible with DHPG. HSV and VZV infections are best treated by acyclovir.
The most frequent opportunistic tumour, Kaposi's sarcoma, is observed in 20% of patients with AIDS. For unknown reasons, KS is observed mostly in homosexuals and its relative incidence is declining. KS is a vascular tumour is in its characteristic form is readily identifiable. In 30 to 40% of patients, the mucosal membrane, most frequently the oral cavity and the larynx, and the internal organs, most frequently the oesophagus, the stomach and the intestines are affected. In most case, no treatment is required. Excision, local treatment with vincristine or laser irradiation are the mainstay of palliative therapy.
Malignant lymphomas of HIV-infected patients differ from other known lymphomas by their localization, degree of malignancy, and response to therapy. HIV-associated lymphomas are frequently found outside the lymphatic system, particularly in the brain, bone marrow, GI tract, and skin. Their response to therapy is much poorer than that of classical lymphomas. The pathogenesis of KS and HIV-associated lymphomas are uncertain. In the case of lymphomas, at least a certain proportion appears to be associated with EBV.
A high percentage of HIV-infected patients shows neurological changes that are not explained by opportunistic infections or tumors. The spectrum of symptoms ranges from slight neuropsychological abnormalities (disturbances of memory, mood and behavior) to organic psychosis and complete dementia. In almost all cases a continuous deterioration is observed. The most frequent neurological disorder is subacute encephalitis (AIDS encephalopathy, AIDS dementia complex) which is seen in two thirds of cases. Other clinical manifestations may be seen, such as acute meningoencephalitis, aseptic meningitis and peripheral neuropathy.
In all stages of HIV infection, characteristic skin manifestations may be observed which frequently may be the first symptoms which lead the patient to seek medical attention. HIV specific conditions include oral hairy leucoplakia and an itching maculopapular eruption. Seborrhoeic eczema occur in 70% of AIDS patients and allergic exanthemas and acne like eruptions are also very common. Viral induced skin eruptions are also frequently seen, such as herpes zoster, cobdylomata acuminatum, verruca vulgaris, molluscum contagiosum.
e. Gastrointestinal Manifestations
Persistent diarrhoea which may be copious in volume, is a frequent problem among these patients. Giardia lamblia, Entamoeba histolytica, Shigella, Salmonella and Campylobacter all cause symptomatic disease. However, appropriate treatment does not always eliminate the watery diarrhoea. Cryptosporadium, CMV, M. avium intracellulare or Kaposi's sarcoma may also be associated with diarrhoea. It had also been suggested that HIV itself may be enteropathic through infection of the mucosal cells and/or through attacking the autonomic nervous supply to the gut.
In children, the clinical spectrum of HIV infection differs from that observed in adults. The typical opportunistic infections of adults are less frequent and bacterial infections predominate. In about 50% of children, a pneumonia is observed which is called lymphoid interstitial pneumonia. It had been suggested that this pneumonia is directly caused by HIV. In addition, failure to thrive, weight loss and neurological symptoms are seen.
HIV transmission to the fetus has been observed as early as the 15th week of pregnancy. Prenatal infection may cause a HIV- specific embryopathy in the majority of infected children. This is characterized by a small forehead, short flat nose, pronounced philtrum, microcephaly, thick lips and hypertelorism. The numbers of newborns infected by their mothers have been rising steadily. The transmission rate from mother to the newborn is estimated at one-third. There is also evidence to suggest that pregnancy also favours the progression of the HIV disease in the mother. The maternal-fetal transmission rate varies geographically from around 15% in Western Europe to up to 50% in Africa. It appears the most important determinant is the virus load present in the mother.
The earliest unambiguously identified HIV-antibody positive serum stems from Kinhasa, Zaire dating back to 1959. It is evident that HIV infection spread unrecognized in the 1960s and 1970s. Over 100,000 cases of AIDS have been reported to the WHO by June 1988. The WHO estimates of all HIV-infected persons ranges from 5 to 10 million. Reliable estimates about the incidence and prevalence of HIV infection do not exist because of the lack of representative data. It is still unclear to what extent the mode of transmission, virus dose, cofactors, and genetic predisposition influence the infection and the incubation period. It is now thought that up to 95-99% of all HIV-infected persons eventually develop AIDS.
Seroconversion - the interval between infection and seroconversion was generally assumed to last about 3 to 12 weeks. Recently, serolatency of many months and up to several years have been recognized in some patients.These observations may have far- reaching implications.
Incubation period - the actual incubation period cannot be predicted in individual cases. The available evidence so far points to an median incubation period of 8 to 10 years (range: a few months to more than 14 years)
Manifestation rate - the percentage of infected persons who finally develop AIDS increases with the duration of the infection by an average of 5 to 7% per year.
Modes of transmission - HIV is transmitted by sexual contact, blood and blood products, or from the mother to the newborn infant. Other theoretical ways of transmission such as by saliva or insects do not play a role in the epidemiology of HIV infection. Evidence is increasing that the infectivity of HIV-infected individuals vary with the course of infection. It appears that infectivity is correlated with viraemia and is greater very early after infection before the appearance of antibodies and later in the course after the development of symptomatic immunodeficiency.
Risk groups - male homosexuals and bisexuals constitute the largest risk group in N. America and Western Europe. Anal intercourse and the multiplicity of partners in the case of homosexuals are the risk factors in the case of homosexuals.In contrast, heterosexual spread is the largest category in developing nations and may be associated with other sexually transmitted disease, particularly those causing genital ulcers. Prostitutes, particularly IV drug-abusing prostitutes are important multiplicators of the epidemic. The infection rate of prostitutes ranges from 0% in some European and American cities to 90% in some African cities.
HIV is transmitted by blood transfusions, clotting factors, and by contaminated needles and syringes. Blood transfusions as a cause of infection have been virtually eliminated in Western Europe and N. America since the introduction HIV antibody screening in 1985 but it continue to be a important cause of HIV transmission, particularly in Central Africa because of the high degree of infection of the donors and the lack of resources to implement the screening of the donor's blood. Infection transmitted via clotting factor have been eliminated since HIV inactivation steps have been included in their production process since 1985. IV drug abusers represent the largest AIDS patient groups in Italy (65%) and Spain (54%) and the second largest group in the US and the majority of Western European countries.
The increase in HIV-infected mothers, mostly drug-dependent is paralleled by an increase of HIV-infected newborns. The transmission rate from infected mothers to their newborn infants is about one-third. Medical personnel are not considered to be a risk group. By April 1988, only 22 cases of medical personnel infected via needle injuries and contact with the blood of HIV-infected persons have been described worldwide.
Incidence and prevalence of HIV infection - no reliable data exist on the incidence and prevalence of HIV infection in the general population. The prevalence of HIV infections in homosexuals in the US ranges from 20% to 70% in some urban centres. On the basis of studies of samples from HIV risk groups and from the general population, the total prevalence of HIV-infected persons has been estimated in several countries. The prevalence of HIV infected persons in the USA was estimated to be 1 to 1.5 million in June 1988.
Africa - HIV infection is not limited to certain risk groups. The male:female ratio is 1:1 in contrast to Western Europe and N. America where the ratio is approximately 13:1. The extent of infection in the general population is considerable in some regions, mainly in the large cities and in some rural areas. In Kinshasa (Zaire) the prevalence of HIV infection was 7% in pregnant women and blood donors in early 1988. The seropositivity rate amongst blood donors in Kigali (Uganda) was 18% in 1984. The highest infection rates were found in prostitutes and in patients with sexually transmitted diseases.
Caribbean and South America - In these countries, the transmission is homosexual and heterosexual. The male:female ratio in Haiti is 4:1, suggesting that heterosexual transmission is important.
Asia and Australia - the prevalence of HIV infection in Asia is rising dramatically, especially in Thailand and India. It is predicted that HIV infection in Asia will outstrip that in Africa in due course. Most of the initial cases stem from Japan and Israel. Transmission was primarily by students from Africa and by contacts of Asian business people abroad. The epidemiology of AIDS in Australia and New Zealand is similar to that of other industrialized countries of N. America and Western Europe.
Several hypothesis regarding the origin of HIV have been developed (1) mutation of older viruses (2) transmission of animal viruses eg. SIV to man (3) transmission by an isolated remote section of the population eg. by change of sexual behavior and mobility. Available data at present favour the third possibility.
1. Serology - the diagnosis of HIV infection is usually based on serological tests.
(a) Antibody tests - ELISAs are the most frequently used method for screening of blood samples for HIV antibody. The sensitivity and specificity of the presently available commercial systems approaches 100% but false positive and false negative reactions occur. Other test systems available include passive particle agglutination, immunofluorescence, Western blots and RIPA bioassays. Western blots are regarded as the gold standard and seropositivity is diagnosed when antibodies against both the env and the gag proteins are detected. The sensitivity of the test systems are currently being improved by the use of recombinant antigens.
Microplate ELISA: coloured wells indicate reactivity
Interpretation of Western blot results for HIV antibody
(b) Antigen tests - HIV antigen can be detected early in the course of HIV infection before the appearance of antibody. It is undetectable during the latent period (antigen-antibody complexes are present) but become detectable during the final stages of the infection. It was argued that the routine use of antigen screening tests in the blood transfusion service may result in earlier cases of HIV infection being identified. However a large scale study carried out in the US failed to show any benefit.
2. Virus isolation - virus isolation is accomplished by the cocultivation of the patient's lymphocytes with fresh peripheral blood cells of healthy donors or with suitable culture lines such as T-lymphomas. The presence of the virus can be confirmed by reverse transcriptase assays, serological tests, or by changes in growth pattern of the indicator cells. However virus isolation is tedious and time consuming (weeks) and is successful in only 70 to 90% of cases. Therefore virus isolation is mainly used for the characterization of the virus.
3. Demonstration of viral NA - this can be accomplished by probes or by PCR techniques. The latter may be useful because of its extremely high sensitivity.
4. Prognostic Tests - the following may be useful as prognostic tests; (1) HIV antigen (2) Serial CD4 counts (3) Neopterin (4) B2-microglobulin. (5) Viral load. Of these tests, only serial CD4 counts and HIV viral load are still routinely used.
a. HIV viral load - It appears that HIV viral load has the greatest prognostic value. HIV viral load in serum may be measured by assays which detect HIV-RNA e.g. RT-PCR, NASBA, or bDNA. HIV viral load has now been established as having good prognostic value, and in monitoring response to antiviral chemotherapy. Patients with a low viral load during the incubation period had a better prognosis than those with a high viral load. Patients whose viral load decreased significantly following the commencement of antiviral therapy had a better prognosis than those who did not respond.Among patients who responded to antiviral therapy, those who had a low pre-treatment viral load had a better prognosis than those who had a high pre-treatment viral load.
b. CD4 counts - despite the increasing use of HIV-RNA assays, measurement of CD4 still has important value in monitoring disease progression and response to antiviral chemotherapy. whereas CD4 count gives an indication of the stage of disease. “The measurement of HIV viral load tells us where the disease is going, whereas CD4 count tells us where the disease is at this moment”
5. Antiviral susceptibility assays
Because of the increasing range of anti-HIV agents available, there is increasing pressure on the provision of antiviral susceptibility assays. There are two types of antiviral susceptibility assays: phenotypic and genotypic assays
Phenotypic assays define whether a particular strain of virus is sensitive or resistant to an antiviral agent by determining the concentration of the drug needed to inhibit the growth of virus in vitro. e.g. Plaque-reduction assay for HSV, plaque-reduction assay for HIV. However, phenotypic assays can only be used for viruses that can be cultivated. Moreover, in the case of HIV, plaque reduction assays may not be that appropriate since not all HIV strains produce plaques in cell culture.
In the case of genotypic assays, mutations that are associated with resistance are assayed for by molecular biology methods such as PCR and LCR. However, these assays are tedious and are not suitable for a routine diagnostic laboratory. Moreover, he results of genotypic assays may prove very difficult to interpret since HIV mutates at a furious pace, and it is also possible that resistant strains are present right at the beginning of infection.
Therapy of HIV is complicated by the fact that the HIV genome is incorporated into the host cell genome and can remain there in a dormant state for prolonged periods until it is reactivated. Effective therapy must be directed against both free virus and virus-infected cells. Although a number of substances with in vitro anti-HIV activity have been described, only a few drugs exhibit anti-HIV activity in vivo at tolerable toxicities. The main group of substances described are;
1. Nucleoside analogues reverse transcriptase inhibitors. AZT, DDC, DDI and lamuvidine.
2. Non-nucleoside analogue reverse transcriptase inhibitors e.g. Nevirapine
3. HIV Protease inhibitors e.g. Ritonavir, Indivavir. They are the most potent inhibitors of HIV replication to date.
Zidovudine (AZT) was the first anti-viral agent shown to have beneficial effect against HIV infection. However, after prolonged use, AZT-resistant strains rapidly appears which limits the effect of AZT. Recent clinical trials reported significant benefit in the use of combination therapy over the use of monotherapy. The rationale for this approach is that by combining drugs that are synergistic, non-cross-resistant and no overlapping toxicity, it may be possible to reduce toxicity, improve efficacy and prevent resistance from arising. In fact, significant success has now been reported for trials involving multiple agents including protease inhibitors. The aim of anti-HIV therapy has now shifted from simply delaying the progression of disease to finding a permanent cure. We have now entered the era of highly active anti-retroviral therapy (HAART).
The current consensus is that one should give a potent combination of agents HAART right from the start when treatment is indicated. The most popular combination is AZT and lamivudine plus a protease inhibitor. Lamivudine has greater anti-retroviral activity that AZT alone and is active against many AZT-resistant strains without significant increase in toxicity.. Among protease inhibitors, indinavir (IDV) is more potent than saquinavir and appears to have fewer drug interactions and short-term adverse effects than ritonavir. In currently recommended doses, AZT prophylaxis is well-tolerated with health workers; short-term toxicity associated with higher doses primarily includes GI symptoms, fatigue, and headache. In HIV-infected adults, 3TC can cause GI symptoms, and rarely pancreatitis. IDV toxicity includes GI symptoms and after prolonged use, mild hyperbilirubinaemia (10%), and kidney stones (4%).Below is a table of some of the drugs available.
It is generally agreed that treatment should be started when CD4<500/ml or viral load >5000 to 10000 copies/ml (bDNA assay). If CD4 count >500/ml but viral load >5000 to 10000 copies/ml (bDNA assay), then recommendations vary. It may then be advisable to treat those who are compliant and committed.
A. Nucleoside Reverse Transcriptase Inhibitor
B. Non-Nucleoside Reverse Transcriptase Inhibitor
C. HIV Protease Inhibitors
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