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Retroviridae. Human immunodefficiency virus

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Chair of Microbiology, Virology, and Immunology
Retroviridae.
Human Immunodeficiency
Virus
Lecturer Prof. S.I. Klymnyuk
The first indication of new disease – Acquired
Immunodificiency Syndrom (AIDS) began in the summer of
1979, when reports came from great city of USA (New York,
Los Angeles, San Francisco) of a sudden increase in the
incidence of two very rare diseases Kaposi's sarcoma (before
registrated only at elderly Africans) and Pneumocystis carinii
pneumonia (before described as epidemics at the closed
children’s establishments) in young adults who were
homosexuals or addicted to heroin or other injected narcotics.
They appeared to have lost their immnune competence,
rendering them vulnerable to overwhelming and fatal
infections with relatively avirulent microorganisms, as well as
to lymphoid and other malignancies.
Pneumocystis carinii
Statistics
Every day in the world infect with HIV 14.000 people,
about 6.000 – young men and women 15 - 24 years old.
• The latest statistics on the world
epidemic(UNAIDS/WHO) - 2005
•
•
•
•
•
•
People living with HIV/AIDS
Adults living with HIV/AIDS
Women living with HIV/AIDS
Children living with HIV/AIDS
New infections with HIV/AIDS
AIDS deaths in 2005
36,6 million
36,3 million
17,3million
2,3 million
4,1 million
2,8 million
New infections
HIV: A Global Pandemic
Eastern Europe
& Central Asia
Western Europe
1.2 – 1.8 million
520
000
–
680
000
North America
East Asia & Pacific
790 000 – 1.2 million
700 000 – 1.3 million
North Africa & Middle
East
South
470 000 – 730 000
& South-East Asia
350 000 – 590 000
Sub-Saharan Africa
4.6 – 8.2 million
25.0 – 28.2 million
Caribbean
Latin America
1.3 – 1.9 million
Australia
& New Zealand
12 000 – 18 000
Adults and children estimated to be living with
HIV/AIDS (2003): 34 – 46 million total
Further statistics
• 48% of adults living HIV/AIDS are women
and 59% in the Sub-Saharan Africa
• 24,5 million of adults and children living with
HIV is in the Sub-Saharan Africa
• Although the Sub-Saharan has just over 10%
of the worlds population but it is close to two
thirds of those who live with HIV/AIDS
NOTE:
• More than 25 million people died of
AIDS since 1981 and AFRICA has more
than 12 million orphans
HIV, the etiologjcal agent of AIDS, belongs to the lentivirus
subgroup of the family Retroviridae. The lentivirus
subgroup (L. lentus = slow) includes the causative agents of
the slow virus diseases visna/maedi in sheep and others.
Besides HIV, the related animal immunodeficiency viruses
also are assigned to this group.
Types of HIV Virus
• HIV 1
– Most common in sub-Saharan Africa and
throughout the world
– Groups M, N, and O
– Pandemic dominated by Group M
 Group M comprised of subtypes A - J
• HIV 2
– Most often found in West Central Africa, parts
of Europe and India
Viral genes and antigens. The genome of HIV contains the
three structural genes (gag, pol and env) characteristic of all
retroviruses, as well as other nonstructural and regulatory
genes specific for the virus. The products of these genes,
both structural and nonstructural, act as antigens. Sera of
infected persons contain antibodies to them. Detection of
these antigenes and antibodies is ofgreat value in the
diagnosis and prognosis of HIV infections.
Virus travels through
Bloodstream
HIV attacks t-cells
Killer t-cells destroy affected
cells
AIDS virus attaches to a CD4
receptor
Transcription
Reverse Transcription
Proteins cut and
packaged with RNA
Possible Infections
Budding new
viruses
The pathogenesis of AIDS is dependent on the biology of
HIV, e.g:
'Trojan horse' mechanism - virus escapes recognition by
replication inside monocytes, from where it can spread to
other tissues and other hosts.
Latency - Lentiviruses do not show true latency (unlike
Herpes viruses or lambda) but do have the capacity to control
the expression of their genome by means of virus-encoded
trans-acting regulatory proteins (tat and rev).
Antigenic variation - new variants continually arise. In other
Lentiviruses such as CAEV, each new antigenic variant
results in a flare up of disease. May also occur in HIV and
contribute to decline of immune system - 'ratcheting'
mechanism due to increasing virus load?
Some of the immune abnormalities in HIV infection
include:
Altered cytokine expression
Decreased CTL and NK cell function
Decreased humoral and proliferative response to antigens and
mitogens
Decreased MHC-II expression
Decreased monocyte chemotaxis
Depletion of CD4+ cells
Impaired DTH reactions
Lymphopenia
Polyclonal B-cell activation
It is not clear how much of the pathology of AIDS is directly
due to the virus and how much is caused by the immune
system itself. There are numerous models which have been
suggested to explain how HIV causes immune deficiency:
Evolution of Antibodies
Window Period
Window Period
• Time from initial infection with HIV until
antibodies are detected by a single test
• Usually 3-8 weeks before antibodies are
detected
• May test false-negative for HIV antibodies
during this time period
• Can still pass the virus to others during this
period
Disease Progression
• Severity of illness is determined by amount
of virus in the body (increasing viral load)
and the degree of immune suppression
(decreasing CD4+ counts)
• As the CD4 count declines, the immune
function decreases.
-blood
-semen
-vaginal fluid
-breast milk
ACQUIRED DEFICIENCY SYNDICOME (AIDS)
Clinical features of HIV infection. AIDS is only the last stage in
the divide spectrum of clinica features in HIV infection.
The natural evolution of HIV infection can be considered in the
following stages:
I. Acute HIV infection. Within a few weeks of infection with
HIV, about 10-15 per cent of persons experience low grade fever,
malaise, headache, 1ymphadenopathy, sometimes with rash and
arthropathy resembling glandular fever.
2. Asymptomatic infection. All persons infected with HIV,
whether they experience seroconversion illness or not, pass
through a phase of symptom1ess infection; lasting for
several months or years. They show positive HIV antibody
tests during this phase and are infectious. In some, the
infection may not progress any further, while in others it
may lead to full brown AIDS, either directly or through
cytopenias, minor opportunistic infection, persistent
generalised lympnadenopathy or AIDS related complex
(ARC) as described below.
3. Persistant Generalised Liphadenopathy (PGL).
This has been defined as the presence of enlarged lymph nodes,
at least 1,0 cm, in diameter, in two or more noncontiguous
extrainguinal sites, that persist for at least three months, in the
absence of any current illness or medication that may cause
lymphadenopathy. This by itself is benign but a proportion of
the cases may progress to ARC or AIDS.
4. AIDS Related Complex (ARC). This group inc1udes
patients with considerable immunodeficiency, suffering from
various constitutional symptoms
or having minor
opportunistic infections. The typical constitutional symptoms
are fatigue, unexplained fever, persistent diarrhea and parked
weight loss of more than 10 per cent of body weight. The
common opportunistic infections are oral candidiasis, herpes
zoster,
salmonellosis
or
tuberculosis.
Generalized
lyrnphadenopathy and splenomegaly are usually present. ARC
patients are usually severely ill and many of them progress to
AIDS in a few months.
5. AIDS. This is the end stage disease representing the
irreversible breakdown of immune defense mechanisms,
leaving the patient a prey to progressive opportunistic
infections and malignancies. The clinical severity of AIDS
varies with the type of infection or malignancy present. In
early AIDS, many patients are ill only during episodes of
infection which may respond to treatment. Between episodes
they may be relatively well and able to resume normal life.
WHO HIV/AIDS Classification System
Stage I
Asymptomatic
Stage II
Minor
Symptoms
Stage III
Moderate
Symptoms
Stage IV
AIDS
According to the system most affected patients present with
various complaints, some of which are as follows:
A. The commonest presentation is with increasing dry cough,
dyspnea and fever. In the USA and other Western countries, the
characteristic pathogen initially was P. carinii but now M.
tuberculosis or an atypical mycobacterium such as M. aviumintracellulare is more often responsible. In the developing
countries, the most important pathogen is M. tuberculosis, with
many strains being multidrug resistant. In fact the poor nations
are facing a double epidemic, jointly with HIV and tuberculosis.
Pneumonia may be viral (CMV) or fungal (cryptococcus,
histoplasma). Recurrent pneumonia is considered to be
indicative of AIDS.
Pneumocystis carinii
Histoplasma capsulatum
B. Gastrointestinal system. The mouth is often involved in
AIDS, with thrush, herpetic stomatitis, gingivitis, Kaposi's
sarcoma. Dysphagia may be due to esophageal candidiasis. A
characteristic intestinal pathogen in AIDS is cryptosporidium.
Salmonellae, mycobacteria, CMV or adenoviruses also
frequently cause intestinal infections. Systemic
strongyloidosis may occur. Chronic colitis is common in male
homosexuals (В«gay bowel syndromeВ»), from which ameba,
lamblia and a host of diarrheagenic bacteria have been
reported.
Candidiasis
Cryptosporidium (intestinal epithelium)
Central nervous system: The typical CNS opportunistic
infections are toxoplasmosis and cryptococcosis. Infections
are also seen with CMV, herpes simplex, papovaviruses,
mycobacteria, aspergillus and Candida. Lymphomas of the
central nervous system are common.
D. Malignancies: Kaposi's sarcoma is the characteristic
lesion seen in male homosexuals. It is an indolent multifocal
nonmetastasising is mucosal or cutaneous tumor, probably of
endothelial origin. The other tumors commonly seen are
lymphomas, both the Hodgkin and non Hodgkin types.
Cryptococcus neoformans (nervous system)
E. Cutaneous. Besides Kaposi's sarcoma, herpes lesions,
candidiasis, xeroderma, seborrheic dermatitis, prurigo,
folliculitis, impetigo and molluscum contagiosumn are
common cutaneous lesions.
The definition of AIDS has since been broadened to include
all seropositive persons (irrespective of clinical
manifestations) with CD4 T cell counts of less than 200 per
mm3.
Dermatomycosis
Herpes zoster
Dermatitis
Herpes
Kaposi's sarcoma
Kaposi's sarcoma
Warts
Sarcoma
Herpetic infection
Р•czema
6. Dementia. HIV may cause direct cytopathogenic damage
in tire central nervous system. It can cross the blood brain
barrier and cause encepfialopathy leading to loss of higher
functions, progressing to dementia.
7. Pediatric AIDS. About one third to one half the number
of babies born to infected mothers are infected with HIV.
Many of them may not survive for a year. Children may also
acquire the infection from b1ood transfusions or blood
products.
Laboratory diagnosis
Laboratory procedures for the diagnosis of HIV infection
include tests for immunodificiency as well as specific tests for
HIV.
A. Immunological tests. The following parameters help to
establish the immunodeficiency in HIV infection:
l . Total leucocyte and lymphocyte count to demonstrate
leucopenia and a lymphocyte count usually below
2,000 /c.mm.
2. T cell subset assays. Absolute T4 cell count will be usually
less than 200/c.mm. T4: T8 cell ratio is reversed.
3. Platelet count will show thrombocytopenia.
4. Raised IgG and IgA levels.
5. Diminished CMI as indicated by skin tests.
6. Lymph node biopsy showing profound abnorma1ities.
B. Specific tests for HIV infection. These inc1ude
demonstration of HIV antigens and antibodies and isolation
of the virus.
I. Antigen detection. The time course of appearance of
detectable antigens and antibodies after VIIV infection is
generally as follows:
Following a single massive infection, as by blood
transfusion, the virus antigens (p24) may be detectable in
blood after about two weeks. IgM antibodies appear in about
4-6 weeks, to be followed by IgG antibodies (Fig. 2).
2. Virus isolation. Once infected with HIV, a person remains
infected for life. The virus is present in circulation and body
fluids, mostly within the lymphocytes but some are also cell
free. Virus titres are high early in infection, about a week
before antibodies start appearing. Antibodies do not neutralize
the virus and the two can coexist in the body.
3. Antibody detection. Demonstration of antibodies is the
simplest and most widely employed technique for the
diagnosis of HIV infection.
Karpas’ test is a slide immunoperoxidase reaction. HIV
infected cells fixed on teflon coated slide wells are treated
first with the test serum and then with horseradish
peroxidase labelled antihuman globulin. Finally, a suitable
substrate is added which gives a colour reaction if the test
is positive. The test is simple and inexpensive but the
evaluation is subjective.
Collection of blood
Blood keeper
IMMUNOPROPHYLAXIS
Several approaches are being used to develop a vaccine for HIV. At
present, there is no safe and effective HIV vaccine.
Types of HIV vaccines
1. Attenuated vaccines are made from genetically engineered
strains lacking some crucial genes, so that the resulting virus causes
a harmless infection. This approach has been tried successfully with
simian immunodeficiency virus (SIV)
2. Killed virus vaccines do not induce protective anti-SlV immunity
in animal trials. However, killed virus vaccines may prevent the
emergence of clinical disease:
- Monkeys vaccinated with killed SIV vaccines are less likely to
develop disease.
- In humans, it has been proposed that vaccination with low doses of
killed HIV enhances cellular immunity and favors (lie development
of cell-mediated cytotoxicity. The benefits of therapeutic
immunization in humans are not known. Evaluation is difficult
because the end-point is a disease-free interval that is long and
variable.
3. Recombinant viral particles made by inserting HIV
glycoprotein genes in, for example, vaccinia-virus genomes
induce neutralizing antibodies in animals. The overall
effectiveness of recombinant vaccinia virus vaccines in
humans has not been established
4. Component vaccines have been prepared from isolated
gpl20, polymerized gpl20, or gpl20 peptides representing
more conserved regions (such as the CD4-binding domain)
Therapy of HIV Infection:
Several distinct classes of drugs are now used to treat HIV infection:
Nucleoside-Analog Reverse Transcriptase Inhibitors (NRTI). These drugs
inhibit viral RNA-dependent DNA polymerase (reverse transcriptase) and
are incorporated into viral DNA (they are chain-terminating drugs).
Zidovudine (ZDV, Retrovir) first approved in 1987
Didanosine (ddI, Videx)
Zalcitabine (ddC, Hivid)
Stavudine (d4T, Zerit)
Lamivudine (3TC, Epivir)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs). In contrast to
NRTIs, NNRTIs are not incorporated into viral DNA; they inhibit HIV
replication directly by binding non-competitively to reverse transcriptase.
Nevirapine (Viramune)
Delavirdine (Rescriptor)
Protease Inhibitors. These drugs are specific for the HIV-1 protease and
competitively inhibit the enzyme, preventing the maturation of virions
capable of infecting other cells.
Saquinavir (Invirase) first approved in 1995
Ritonavir (Norvir)
Indinavir (Crixivan)
Nelfinavir (Viracept)
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