1. term Acquired Immunodeficiency Syndrome. In 1983 Barre-Sinoussi and

 1. Human Immunodeficiency Virus

Definition, history and nature of the HIV and AIDS

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Immunodeficiency Syndrome of humans is caused by two lentiviruses (belonging to
retrovirus family), human immunodeficiency viruses types 1 and 2 (HIV-1 and
HIV-2).  Both viruses are the result of
multiple cross-species transmissions of simian immunodeficiency viruses (SIVs)
naturally infecting African primates.

was first discovered as a new disease in 1981 when increasing numbers of
homosexual men was found to complain to unusual opportunistic infections like
Pneumocystis jiroveci and other rare malignancies. 12

1982, before discovery of etiologic agent and diagnostic tests which allow to
detect antibodies against infectious factor, CDC used for the first time term
Acquired Immunodeficiency Syndrome. In 1983 Barre-Sinoussi and Montagnier
isolated HIV and in 1985 there was developed first useful diagnostic test. 1986
brought the first drug against HIV infection – Zidovudine (also known as


1.2. Etiologic agent


differs retroviruses from other RNA viruses is presence of Reverse Transcriptase
Enzyme, which convert a single stranded viral RNA into double stranded DNA and
replacing original genetic information of the human cell.

are two distinct groups of retroviruses causing either directly or indirectly
cause cytopathic effects: the human T lymphotropic viruses (HTLV-1 and HTLV-2),
which are transforming retroviruses; and the human immunodeficiency viruses,
HIV-1 and HIV-2.

was found a retrovirus HIV-1  is a
causative agent of one of the most devastating infectious disease in recent
history. Although HIV-1 and HIV-2 belong to the same family they are different
two different viruses. HIV-1 is responsible for 95% of all HIV infections.

the contrary to HIV-1 which is has differentiated world geographical
distribution, HIV-2 infection progresses slower, with lower risk of developing
AIDS and is mainly associated with west African countries and spread to the
rest of the world is negligible. 6




1.2.1.  Morphology

HIV virion is an icosahedral structure coated externally by two envelope
proteins – the external gp120 and the transmembrane gp41 which form spiky
surface appearance of the virion. The virion buds form the surface of the
infected cell and incorporates a variety of host proteins, including major
histocompability complex class I and II antigens.

core of the virion containing p7 nucleoprotein, the major capsid protein p24 is
cone-shaped and the outer capsid protein p17 is set between capsid and the
envelope. Genetic material of virus consists of two positive-sense, single
stranded RNA genome in the capsid complexed with p7 protein.

 The p17 protein directs entry of the double
stranded DNA provirus into the nucleus and is essential for the process of
virus assembly.

viral capsid are also incorporated three enzymes. The Reverse Transcriptase and
Integrase enzymes which are essential for synthesis of viral DNA and its
integration with host cell chromosomes, and Protease enzyme required for viral

Figure 1. Morphology of HIV 7


1. 3. Classification


are two main classifications of HIV infection established by CDC and WHO based
on clinical features and laboratory results.


1.3.1. WHO classification

staging is used once HIV infection has been confirmed by serological and/or
virological evidence. This staging is especially useful at the time of the first
diagnosis of HIV infection or entry into long-term therapy and also in the
follow up of patients. It should be used to guide decision on starting
prophylaxis or antiretroviral therapy particularly if CD4 count is not

–  associated symptoms

clinical stage










1. WHO clinical
staging of established HIV infection4


However the standard of classification is represented
by immunological assessment – the CD4 count as the pathogenesis of HIV
infection is directly connected to the decrease 
in the number of  T cells that
bear CD4+ receptors.

The immune status of the subject is assessed by
measuring absolute number of CD4+ or percentage of them and considered as the
standard way for estimating severity of immunodeficiency as progression of  HIV infection is associated with progressive
depletion of CD4+T cells.


-related CD4 values

– associated immunodeficiency

<11 months (%CD4+) 12-35 months (%CD4+) 36-59 months (%CD4+) >5 years (absolute
number mm3 or %CD4+)

None or not significant
















<25 <20 <15 <200 or <15%    Table 2. WHO immunological classification for established HIV infection4   1.3.2. CDC classification   Laboratory criteria for defining a confirmed case now accommodate new multitest algorithms, including criteria for differentiating between HIV-1 and HIV-2 infection and for recognizing early HIV infection. A confirmed case can be classified in one of five HIV infection stages (0, 1, 2, 3, or unknown). If there was a negative HIV test within 6 months of the first HIV infection diagnosis, the stage is 0, and remains 0 until 6 months after diagnosis. A. Otherwise, if a stage-3-defining opportunistic illness(table 3) has been diagnosed, the stage is 3. B. Otherwise, the stage is determined by the CD4 test immunologic criteria shown in the following table: Stage Age on date of CD4 T-lymphocyte test <1year 1-5 years 6 years through adult Cells/µL % Cells/µL % Cells/µL % 1 ?1500 ?34 ?1000 ?30 ?500 ?26 2 750-1499 26-33 500-999 22-29 200-499 14-25 3 <750 <25 <500 <22 <200 <14   Table 3. Laboratory CDC staging criteria based on CD4+T loss. 5   C. If none of the above apply (e.g., because of missing information on CD4 test results), the stage is U (unknown). Developing one of the opportunistic infections listed below directly classifies third stage of HIV infection - AIDS. Bacterial infections, multiple or recurrent Candidiasis of bronchi, trachea, or lungs Candidiasis of esophagus Cervical cancer, invasive† Coccidioidomycosis, disseminated or extrapulmonary Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (>1 month’s duration)
Cytomegalovirus disease (other than liver, spleen, or nodes), onset at
age >1 month
Cytomegalovirus retinitis (with loss of vision)
Encephalopathy attributed to HIV§
Herpes simplex: chronic ulcers (>1 month’s duration) or bronchitis,
pneumonitis, or esophagitis (onset at age >1 month)
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1 month’s duration)
Kaposi sarcoma
Lymphoma, Burkitt (or equivalent term)
Lymphoma, immunoblastic (or equivalent term)
Lymphoma, primary, of brain
Mycobacterium avium complex or Mycobacterium kansasii, disseminated or
Mycobacterium tuberculosis of any site, pulmonary†, disseminated, or

2 List of opportunistic infections. 4


Mycobacterium, other species or unidentified species, disseminated or
Pneumocystis jirovecii (previously known as “Pneumocystis carinii”)
Pneumonia, recurrent†
Progressive multifocal leukoencephalopathy
Salmonella septicemia, recurrent
Toxoplasmosis of brain, onset at age >1 month
Wasting syndrome attributed to HIV

Table 4. List of opportunistic infections (continuation). 5



2. Epidemiology


infection/AIDS is a global pandemic, with cases reported from every
country.  The current estimate of the
number of cases of HIV infection among adults worldwide is approximately 37
million, two-thirds of whom are in sub-Saharan Africa of which 50% of cases are
women. In addition, an estimated 2.5 million children younger than age 15 are
living with HIV/AIDS. Every year around 2 million of new infections and 1-1.5
million AIDS related deaths are globally recorded.

of infection is different due to development of the countries, economic status,
self-aware and culture differences. According to regional HIV statistics made
in 2016 by UNAIDS there were these number of people living with HIV in:

and Middle East: 25,9 million (1 180 000 new HIV infections)

and Pacific: 5,1 million (270 000 new HIV infections)

America and Caribbean: 2,1 million (115 000 new HIV infections)

Europe and central Asia: 1,6 million (190 000 new HIV infections)

and Central Europe and North America: 2,1 million (73 000 new HIV infections)



Spread and replication
of the virus in human body

mucosal membrane has been exposured, HIV uses CD4-T lymphocytes or antigen presenting
cells for transport to lymph nodes where site of infection is established. The
antigen presenting cells by its receptors facilitate capture and transport of
the virus. At this point virus gains ability to spread widely through blood.10


Replication cycle

process can be divided into two phases with several steps. Phase one consists
of viral entry, reverse transcription, and integration into host genome. Phase
two includes the synthesis and processing of viral genome changing the host cell
into machinery for transcription and protein synthesis of virulent content.

of HIV to a specific cell surface receptor is accomplished by gp120
preferentially to CD4- receptor molecule. Thus, the virus infects all cells containing
this molecule – lymphocytes, monocytes, antigen presenting cells. But for entry
of virus into cell additional co-receptor is required. Such receptor is
originally expressed as chemokine (CCR5 and CXCR4) by macrophages and
T-lymphocytes. Binding to a co-receptor activates the viral gp41, triggering
fusion between the viral envelope and the cell membrane.

the virus penetrate into cell and uncoat its content, reverse transcription RNA
to DNA by reverse transcriptase enzyme in cytoplasm must occur resulting in a
provirus. This process is susceptible to errors and therefore multiple
mutations occur in ongoing replications. This is the reason of rapidly
progressing drug resistance. 710

Figure 2. Life cycle of HIV 9

Consecutive step is integration of the provirus into
host cell DNA. With the aid of p17 the provirus is transported into nucleus. In
the nucleus, viral integrase enzyme cleaves chromosomal DNA and incorporate the
provirus into host genome. At this moment the provirus is transcribed into
full-length mRNA.

following step is using host DNA as a template to transcribe new RNA copies,
which are processed and exported from nucleus into cytoplasm (to form genomes
or viral proteins). The viral mRNA copies are translated into viral peptide
chains. Viral protease enzyme cleaves polypeptide chains forming new viral
structural elements.

last step of replication cycle is migration to the plasma membrane where
assemble is completed. Once the maturation is finished, the virion buds from
the surface ready to infect another cell and to repeat the whole cycle again.610


2.3. Route
of transmission

   Despite the fact that HIV can be isolated from most of
body fluids and tissue, the majority of infections are transmitted by semen,
cervical secretions, breast milk and blood but there are no evidence for
spreading of infection by social, household contact or by blood-sucking bug as
mosquitoes and bed bugs.

the risk of infection is necessary to mention the exposure factor (integrity of
the exposed site, the type and volume of body fluid and the viral load).

majority of infections are caused by sexual intercourse (vaginal or anal) act
possible as for heterosexual as for men who has sex with men. Passage of HIV
appears to be more efficient from men to women, and to the receptive partner in
anal intercourse, than vice versa. In central and sub-Saharan Africa the
epidemic has always been heterosexual and more than half the infected adults in
these regions are women.

route of acquisition is use of contaminated needles and syringes shared during
intravenous drug misuse is still popular problem (~7% of all HIV infections)
but due to successful education the trend is decreasing. Among the healthcare
workers the risk of infections is estimated for 0,3%.

example is blood, blood products and organ donations in parts of the world
where these products might not be screened and in areas where HIV infections
rate is very high, transfusion associated transmission continues to occur.

The last route of transmission is vertical
transmission – mother-to-child via transplacental, perinatal and breast-feeding
route. European studies suggests that, without intervention, 15% of babies born
to HIV-infected mother are likely to be infected, although rates up to 40%  have been reported in Africa and the USA. 8



Vertical (mother-to-child) transmission of HIV

worldwide number of HIV infections in children is estimated at 3,3 million of
cases which of  90% of cases is reported
in Sub-Saharan Africa (2.9 million).

most common route of transmission in children is vertical transmission (about
90%), youths and older children can be infected the same route of transmission
as adults. Risk of vertical transmission in natural labour is estimated at
15-30%. If baby is breastfed  longer than
6 months the risks increases up to 50% what is observed especially in
developing countries for example in Africa due to necessity of breastfeeding
due to poverty of people.

70% of mother-to-child transmission of HIV is in perinatal period in uterus
(transplacentally or by infection of amniotic membrane and fluid) or  during labour.89



Risk factors supporting vertical transmission

of vertical transmission is highly dependent on mechanism and timing of HIV
transmission which due to multifactorial aspects remains not fully understood
and do not allow to fully estimate the risk of infection.

natural delivery infant is in contact with amniotic fluid, maternal blood,
cervico-vaginal secretions as it travels through birth canal. For that reason
it is important to monitor level of 
viraemia (more than 105 copies of virus per ml increases risk of
infection up to 40%) as it is the most significant risk factor. Additional risk
factors are low level of lymphocytes T-CD4, some systemic diseases or
uro-genital infections, placentas dysfunctions, bleeding, procedures performed
during pregnancy (for example amniotic puncture).

the child is born other maternal pathologies should be consider, for instance –
mastitis, cracked nipples, breast abscess, milk pathology amd by the side of
the child oral candidiasis. 9




Viral factors in vertical transmission of HIV

higher viral RNA load in blood of the mother the higher risk of transmission it
to the child. Undergo of antiretroviral therapy by HIV infected mothers decrease
the viral load and helps to achieve very low vertical transmission rates.
Despite of usage antiretroviral therapy, decreasing viral load below the limit
of detection(in blood, tissue and genital secretions), it has been not it
identified threshold that transmission is not occurring.11

factor which can increase risk of vertical HIV transmission by increasing
maternal viral RNA load prenatally is unprotected intercourse with infected
person during pregnancy resulting primary HIV infection or acquiring other
sexually transmitted disease able to increase viral load in those already were

to viraemia, genital tract and genital tract secretions are strongly associated
with HIV transmission mother-to-child transmission. Yet the local cleansing
with virucidal agents during pregnancy do not show benefit in decreasing the transmission.

viral load during breastfeeding is associated with postnatal transmission.1617


2.3.4.  Immune factors of mother in

immune chemokines of B-cell lymphocytes are natural ligands of viral
coreceptors and may have potential for inhibition of HIV-1 infection. These
chemokines CCL3, CCL4 and CCl5 are natural ligands for CCR5 and are
overexpressed in exposed uninfected infants what suggests their role in
mediation of inhibition of vertical transmission.18

humoral immune response seems to be important impact on mother-to-child
transmission. Although preceding studies showed increased level of maternal
immunoglobulin type G did not protect against vertical transmission some
studies consider them involved into neutralization during transmission at some
level but other studies deny this theory.19

transmission to child is characterized by acquisition of homogenous
quasispecies or variants, yet the factors are still unclear. In another study
perinatally enveloped variants has been found to become selectively neutralized
by maternal autologous antibodies what suggest these antibodies exert changes
on the transmitted HIV virus. According to the authors of this study maternal
autologous antibody ‘can exert powerful protective and selective effects in
perinatal HIV transmission and therefore has important implications for vaccine

has been found in  groups of HIV exposed individuals
counting in infected mothers and their uninfected infants specific cytotoxic
immune response though yet its mechanism in clearance and prevention from
transmission is not fully comprehended. 21

some studies investigated infected mothers were associated with protection
against transmission during labour and breastfeeding but the range, mechanisms
and significance are still unresolved issue. 22

search for the essential influencing factor that could help prevent transmission
is still leading an issue among scientists. One study consider the specific
immune response and especially  suppressive
T lymphocytes  are associated with
exposed uninfected children.23

study  suggests that exposure to low
levels of antigen may be responsible for priming the protective immune responses.
These findings suggest that infants who are able to develop apparently
protective HIV-1-specific cellular immune responses have immunological features
and viral exposure histories that makes them differ from the non responding
infants, giving the all new insights into development of HIV protective
immunity. 24