This document provides an overview of HIV/AIDS, including its classification, transmission, epidemiology, virology, pathogenesis, and treatment. Key points include: - HIV is a lentivirus that infects CD4+ cells and integrates into the host genome. It has high genetic diversity and can lie dormant for years. - HIV is transmitted sexually, through blood exposure, or mother-to-child. Factors like behavior patterns, condom use, and availability of treatment impact spread. - HIV evades the immune system through rapid mutation, hiding in sanctuaries, and immune activation leading to exhaustion. This allows the virus to persist despite immune responses. - HIV causes

1. HIV/AIDS
Dr Abdu A

2. Outlines
 Introduction
 Epidemiology
 Virology
 Pathogenesis & Natural history
 Diagnosis
 Staging
 Treatment

3. Classification of HIV
 HIV class: Lentivirus
 Retrovirus: single stranded RNA transcribed to double stranded
DNA by reverse transcriptase
 Integrates into host genome
 High potential for genetic diversity
 Can lie dormant within a cell for many years, especially in
resting (memory) CD4+ T4 lymphocytes
 HIV type (distinguished genetically)
 HIV-1 -> worldwide pandemic
 HIV-2 -> isolated in West Africa; causes AIDS much more
slowly than HIV-1 but otherwise clinically similar

4. Transmission
 Modes of infection
 Sexual transmission at genital or colonic mucosa
 Blood transfusion
 Mother to infant
 Accidental occupational exposure

5. Factors affecting the spread of HIV
 Sexual behaviour patterns
 Stable/ unstable relationship patterns
 Status of women
 Condom use
 Stigma/discrimination
 Vulnerable population groups
 Distribution of resources
 Availability of education/ testing
 Availability of prevention programs/ resources
 Availability of treatment

6. EPIDEMIOLOGY....
 Overall growth of the global AIDS epidemic appear to have
stabilized.
 Annual number of new HIV infections has been steadily
declining since late 1990s(1999).
 Fewer AIDS related deaths due to significant scale up of ARV
therapy particularly in low & middle income countries.
 However levels of new infections are still high & the gains are
fragile.
 With significant reduction in mortality the number of PLWH
worldwide has increased.

8. Characteristics of HIV
 HIV infect cells that express CD4 receptor molecules
 CD-4 receptor molecules are expressed by T-helper cells and
monocyte-macrophage cell lines
 Successful entry of the virus to a target cell also requires cellular
co-receptors
 CCR5 and CXCR4 are chemokine receptors that are expressed
on T cells, macrophages, and dendritic cells.
 These molecules normally act as receptors for chemokines,
proinflammatory chemicals that are released in the setting of inflammation.
 are expressed on different cell types.

9. Life Cycle of HIV: Replication
 Reverse transcription converse HIV RNA into proviral DNA
 Importation to cell nucleus
 Integration of proviral to host-cell DNA
 Cellular activation causes transcription (copying) of HIV
DNA back to RNA
 Some RNA translated to HIV proteins
 Other RNA moved to cell membrane
 HIV assembled under cell membrane and budded from cell
 Proteases convert immature to infectious HIV

14. Cell cytoplasm
Cell nucleus

16. HIV lifecycle

17. Viral-host Dynamics
 About 1010 (10 billion) virions are produced daily
 Average life-span of an HIV virion in plasma is ~6
hours
 Average life-span of an HIV-infected CD4 lymphocytes
is ~1.6 days
 HIV can lie dormant within a cell for many years,
especially in resting (memory) CD4 cells, unlike other
retroviruses

18. Immunology and HIV
Infection, pathogenesis

19. Viral Entry & Dissemination
 The events associated with the primary HIV infection are
critical determinants of subsequent course of HIV disease.
 Initial infection of susceptible cells vary with the route of
infection.
 Dendritic cells & LCs play an important role in initiation of HIV
infection.

20.  DC cells important for the local replication &carry the
virus to regional LN where CD4+Tcells are infected &
activated,
 Dissemination to other lymphoid tissues via blood
stream including GALT.
 Massive depletion of CD4+ T cells in the GALT.
 Acute burst of viremia-acute HIV syndrome.
 Rapid viral replication in CD4+ T cells precedes HIV
specific immune response resulting in burst of viremia
associated with seeding of the virus.

21.  Initial level of viremia doesn’t determine the subsequent
disease progression, but the steady state plasma viremia at
6mo-1yr.
 Seeding of the virus into lymphoid tissue &other sanctuaries
early in the infection is one of the defining phenomenon for
the chronic & persistent HIV infection.

23. Intracellular
infection
Naïve
B-Cell
Naïve
T8 cell
Naïve T4
helper cell
MHC I presentation
of endogenous
antigen MHC II
presentation of
exogenous antigen
Cell-mediated
(CTLs)
Humoral
(plasma cells /
antibodies)
Free antigen
Th1 Th2
Overview of Adaptive Immune
Response Extracellular
infection
APC
Diagram courtesy of Dr. Samuel Anderson

24. Viral-host Interactions:
 Host: mounts HIV-specific immune responses
 Cellular (cell-mediated) - most important
 Humoral (antibody-mediated)
 Virus: subverts the immune system
 Infects CD4 cells that control normal immune responses
 Integrates into host DNA
 High rate of mutation
 Hides in tissue not readily accessible to immune system
 Induces a cytokine environment that the virus uses to its own
replicative advantage
 Achieved by “activation” of the immune system

25. Cellular Immune Responses to HIV
 CD8 Cytotoxic T lymphocyte (CTL)
 Critical for containment of HIV
 Derived from naïve T8 cells, which recognize viral
antigens in context of MHC class I presentation
 Directly destroy infected cell
 Activity augmented by Th1 response

26. Cellular Immune Responses to HIV
 CD4 Helper T Lymphocyte (Th)
 Plays an important role in cell-mediated response
 Recognizes viral antigens by an antigen presenting cell (APC)
 Utilizes MHC class II
 Differentiated according to the type of “help”
 Th1 - activate Tc (CD8) lymphocytes, promoting cell-mediated immunity
 The Th1 response is mediated by certain interleukins such IL-2,
interferon-gamma (IFN-gamma), and tumor necrosis factor-beta (TNF-
beta)
 Th2 - activate B lymphocytes, promoting antibody mediated immunity

27. Humoral Immune Response to HIV
 Antibodies have many roles in HIV infection but overall
they appear to be less effective in controlling HIV
infection compared to cellular immunity.
 Neutralization
 Antibodies bind to surface of virus to prevent attachment to target cell
 Antibody-dependent cell-mediated cytotoxicity (ADCC)
 Fc portion of antibody binds to NK cell
 Stimulates NK cell to destroy infected cell

28. Evasion of immune system
 So why doesn’t this immune response clear the infection?
1)Viral diversity via mutation & recombination
 Makes (1010 ) 10 billion copies/day -> rapid mutation of
HIV antigens
2)The principal targets of neutralizing antibodies
against HIV are the envelope proteins gp120 and
gp41.
 Hyper variability of the envelope
 extensive glycosylation(glycan shield) of the envelope
 conformational masking of neutralizing epitopes

29. Evasion of immune system
3) Loss of activated T cells including HIV specific CD4+ T cells in
the GALT-40-70%.
 (40–70% of all memory CD4+ T cells in the GALT are
eliminated during acute infection.)
 Impairs Th1 response of CD4 helper T lymphocyte
4) Immune activation - exhaustion of immune system, particularly
HIV specific clones of CD8+ T cells-dysfunction or deletion.
5) Down-regulation of MHC-I molecules on the surface of HIV
infected cells( nef-HIV).
6) Integrates into host DNASequestration of infected cells in the
immunologically privileged sites eg.CNS

30. Pathogenesis of HIV

31. Pathogenesis of HIV...
 HIV infection is a disease characterized by a
profound immunodeficiency from progressive
decline of T-helper cells
 The pathogenetic mechanism of HIV disease is
multifactorial and multiphasic and it differs in
different stage of the disease

32. Cells Infected by HIV
 Numerous organ systems are infected by HIV:
 Brain: macrophages and glial cells
 Lymph nodes and thymus: lymphocytes and dendritic cells
 Blood, semen, vaginal fluids: macrophages
 Bone marrow: lymphocytes
 Skin: langerhans cells
 Colon, duodenum, rectum: chromaffin cells
 Lung: alveolar macrophages

33. General Mechanisms of HIV
Pathogenesis
 Direct injury
 Nervous (encephalopathy and peripheral neuropathy)
 Kidney (HIVAN = HIV-associated nephropathy)
 Cardiac (HIV cardiomyopathy)
 Endocrine (hypogonadism in both sexes)
 GI tract (dysmotility and malabsorption)
 Indirect injury
 Opportunistic infections and tumors as a consequence of
immunosuppression

34. Immune Dysfunction in HIV
 All elements of immune system are affected
 Advanced stages of HIV are associated with substantial
disruption of lymphoid tissue
 Impaired ability to mount immune response to new antigen
 Impaired ability to maintain memory responses
 Loss of containment of HIV replication
 Susceptibility to opportunistic infections

35. Mechanisms of CD4
Depletion and Dysfunction
 Direct
 Elimination of HIV-infected cells by virus-specific immune
responses
 Loss of plasma membrane integrity because of viral budding
 Interference with cellular RNA processing
 Indirect
 Syncytium formation
 Apoptosis
 Autoimmunity

36.  Syncytium Formation
 Observed in HIV infection, most commonly in the brain
 Uninfected cells may then bind to infected cells due to viral gp
120
 This results in fusion of the cell membranes and subsequent
syncytium formation.
 These syncytium are highly unstable, and die quickly.

37. Immune Activation, Inflammation, and HIV
Pathogenesis
 Activation of the immune system and inflammation are
essential components of any appropriate immune response to a
foreign antigen.
 HIV induces immune activation -- which may seem
paradoxical because HIV ultimately results in severe
immunosuppression
 Endogenous factors (cytokines), and a number of exogenous
factors(other microbes) that are associated with heightened
cellular activation can enhance HIV replication and thus may
have important effects on HIV pathogenesis.

38. Immune Activation, Inflammation…..
 Immune activation and inflammation in the HIV-infected
individual contribute substantially to
 the replication of HIV,
 the induction of immune dysfunction, and
 the increased incidence of chronic conditions associated
with persistent immune activation and inflammation

39.  From a virologic standpoint, although quiescent CD4+ T
cells can be infected with HIV, reverse transcription,
integration, and virus spread are much more efficient in
activated cells.
 Furthermore, cellular activation induces expression of
virus in cells latently infected with HIV.
 In essence, immune activation and inflammation provide
the engine that drives HIV replication.
 This effect can persist even after the HIV viral load is
brought to <50 copies/mL by cART.

40. Microbial Translocation and Persistent Immune
Activation
 One proposed mechanism of persistent immune activation
involves the disruption of the mucosal barrier in the gut due
to HIV replication in and disruption of submucosal lymphoid
tissue.
 As a result of this disruption, there is an increase in the
products, particularly lipopolysaccharide (LPS), of
bacteria that translocate from the bowel lumen through the
damaged mucosa to the circulation, leading to persistent
systemic immune activation and inflammation.

41. Persistent Immune Activation and Inflammation in
HIV
 As survival of HIV-infected individuals increase
 complications relate to chronic immune activation and
inflammation are seen in increased frequency.
 Most important : endothelial cell dysfunction and CV disease.
 Other chronic conditions reported include
 bone fragility,
 certain cancers,
 persistent immune dysfunction,
 diabetes,
 kidney and liver disease, and neurocognitive dysfunction,
 an overall picture of accelerated aging.

42. Consequence of Cell-mediated
Immune Dysfunction
 Inability to respond to intracellular infections
and malignancy
 Mycobacteria, Salmonella, Legionella
 Leishmania, Toxoplama, Cryptosporidium,
Microsporidium
 PCP, Histoplamosis
 HSV, VZV, JC virus, pox viruses
 EBV-related lymphomas

43. Natural History of HIV Infection

44. Typical course of an untreated HIV-infected
individual

45. Primary HIV Infection
 Following primary infection there is initial viremia
 The phenomena of dissemination of virus to lymphoid
organs is the major factor in establishment of chronic
and persistent infection
 Whatever the route of entry the virus, it reaches a
lymphoid organ, where it bases itself and replicates
extensively
 Intense replication brings about a burst of viremia which
triggers HIV-specific antibody

46. Viral-host events
in primary HIV infection:
 Initial viral inoculation, replication
and dissemination with high levels
of viremia.
 Peak viremia 1-2 weeks after onset
of symptoms.
 Dissemination to lymphoid and
other tissues: HIV RNA found in
saliva, genital secretions within first
month after onset of symptomatic
illness.
Kahn and Walker, NEJM 1998 339:33-39

47. Acute retroviral syndrome (2/3 of pts)
 Acute viral illness – abrupt onset
 Fever up to 400 (80-90% of symptomatic pts)
 Malaise, anorexia, wt loss
 Myalgias, arthralgias
 Headache, pharyngitis, rash (less than ½)
 Assess risk factors
 Physical exam:
 Lymphadenopathy, oral or genital ulcers
 Meningeal signs, rarely CN palsies or GBS
 Thrush (usually mild)

48. Patterns of HIV Disease Progression
HIV
Infection
Long-term
Non-progressors
Rapid Progressors
Typical Progressors
<3 years
7-10 years
>10-20 yr
Normal, Stable CD4
85- 90 %
<5 %
<10 %

49. Chronic and Persistent Infection
 HIV-specific antibody partially clears the virus
 There is clinical latency but there is no virological latency
 Initial clones of CD8 lymphocytes CTLs, which partially
control viremia, are later lost
 There is progressive drop in CD4 T-cells

50. Advanced HIV Disease
 CD4 cells fall below critical level: <200cells/ml
 Patients present with OIs or malignancy
 Higher degree of viremia due to destruction of
lymphoid organs

51. Diagnostic studies

52. Diagnosis
 Voluntary testing program
 Risk groups
 community
 “routine” screening
 Blood donation
 IVF, transplant donor/ recipient
 Physician-initiated testing
 Acute HIV-like illness
 Opportunistic infection
 Epidemiological risk factors

53. Laboratory Tests for Diagnosis
 Detection of Antibody
 Rapid tests
 ELISA
 Western blot
 Direct detection of virus
 Viral culture
 Viral Load / RNA or DNA PCR
 ANTIGEN (Ag) in plasma/serum (p24)
 CD4: follow up/ “staging” on diagnosis/ not for Dx
AVAILABLE IN MOST SETTINGS

54. Rapid Tests
• Various tests that provide results in ~10-20 minutes
• Sensitivity approaches 100%; specificity is high as well
• Negative tests can be reported as negatives
• Positive results should be confirmed
• Different types available (agglutination, immunofiltration…)

55. Window Period
 Time period between acquisition of HIV infection
and formation of detectable levels of
ANTIBODIES (Ab)
 At 6 weeks: 80% will have detectable antibodies
 At 12 weeks almost 100%
 Rare cases will take longer

56. Laboratory Markers of HIV Infection
 Viral load
 Marker of HIV replication rate
 Number of HIV RNA copies/mm3 plasma
 CD4 count
 Marker of immunologic damage
 Number of CD4 T-lymphocytes cells/mm3 plasma
 Median CD4 count in HIV negative Ethiopians is significantly lower
than that seen in Dutch controls
 Female 762 cells/mm3 (IQR 604-908)
 Male 684 cells/mm3 (IQR 588-832)

57. CD4 T-cell Count and Progression to AIDS
 In contrast to VL, baseline CD4 is not a good predictor
of time to progression to AIDS
 However, as the CD4 count declines over time,
patients will develop opportunistic infections
 Develop in a sequence predictable according to CD4 count
 WHO Staging system

58.  The WHO clinical staging system includes:
 A clinical classification system
 A laboratory classification to categorize the
immunosuppression of adults by their total
lymphocyte counts or CD4
 This staging system has proven reliable for predicting
morbidity and mortality in infected adults
 The WHO Clinical Staging System is based on clinical
markers believed to have prognostic significance resulting in
four categories
WHO Clinical Staging System
The WHO staging system is not 100% sensitive and specific!

59. Classification Systems for HIV Infection
and Disease
 Require a positive HIV test
 Reflect the progressive nature of HIV disease from
asymptomatic to AIDS
 Hierarchical: once in a stage cannot go back to an
earlier stage without treatment
 Staging reflective of prognosis and ?CD4 counts (level
of immunity)

60. WHO Clinical Staging System
Clinical Stage 1
• Asymptomatic infection
• Persistent generalized lymphadenopathy (PGL)
Definition of PGL:
swollen or enlarged lymph nodes > 1cm,
in 2 or more non-contiguous extra-inguinal sites,
in absence of known cause; lasting more than 3 month

61. Clinical Stage 2
 Unexplained Weight loss <10% of presumed body weight
 Minor mucocutaneous manifestations:
 Papular pruritic eruptions
 Seborrhoeic dermatitis
 Angular chelitis
 Fungal nail infections of fingers
 Recurrent oral ulcerations (≥ 2 x/6months)
 Herpes zoster (current or in last 2 years)
 Recurrent upper respiratory tract infections (sinusitis, otitis
media, pharyngitis)

62. Stage 2
Herpes Zoster

63. Stage 2
Papular pruritic
eruption
Always exlcude scabies, insect bites

64. Severe molluscum contagiosum

65. Stage 2
Seborrhoeic
dermatitis
Itchy scaly skin condition, especially affecting scalp, face,
upper trunk (also common in non-HIV)

66. Angular
stomatitis
Splits or cracks on lips at angle of mouth

67. Clinical Stage 3
Oral candidiasis
Unexplained Weight loss >10%
Recurrent vaginal candidiasis
Oral hairy leukoplakia
Pulmonary tuberculosis (Current)
Unexplained chronic diarrhoea > 1 month
Unexplained prolonged fever (intermittent or constant
for >1 month)

68. Severe presumed bacterial infections (e.g. pneumonia, empyema,
pyomyositis, bone or joint infection, meningitis, bacteremia)
Acute necrotizing ulcerative stomatitis, gingivitis or periodontitis
Unexplained:
Anaemia (<8g/dl) or
Neutropenia (<500/mm³) or
Thrombocytopenia (<50 000/mm³)
For > 1 month
Clinical Stage 3

69. Oral thrush

70. Oral hairy leukoplakia

71. Necrotising
stomatitis

72. Clinical Stage 4
Recurrent severe bacterial pneumonia
Chronic herpes simplex infection orolabial, genital, or
anorectal of > 1 month duration
Cytomegalovirus infection (other than liver, spleen, LN)
CNS toxoplasmosis

73. Clinical Stage 4
HIV wasting syndrome
Pneumocystis pneumonia
Candidiasis of the oesophagus
Extrapulmonary tuberculosis
Kaposi's sarcoma
Cryptococcal meningitis (or other extra pulmonary
crypto)

74. Clinical Stage 4
Invasive cervical carcinoma
Cryptosporidiosis, Isosporiasis
HIV encephalopathy
Progressive multifocal leukoencephalopathy (PML)
Candidiasis of trachea, bronchi, or lungs
Any disseminated endemic mycosis Histoplasmosis,
Coccidiomycosis, Penicilliosis

75. Clinical Stage 4
 Disseminated Mycobacterial diseases other than
tuberculosis
 Recurrent non-typhoidal salmonella septicaemia (2
or >episodes in one year)
 Lymphoma (cerebral or B-cell non-Hodgkin)
 Leishmaniasis, visceral
 Visceral Herpes simplex
 HIVN
 Entropathy…..

76. HIV wasting: definition
Weight loss > 10%
PLUS
Unexplained chronic diarrhoea
> 1 month
OR
Unexplained prolonged fever
> 1 month

77. PCP

78. Kaposis Sarcoma

79. Kaposis
Sarcoma

80. Kaposi’s sarcoma

81. Kaposis
Sarcoma

82. Lymphoma

83. Antiretroviral Therapy

84. What are Anti Retroviral Drugs ?
 drugs which ‘try’ to halt the viral replication by acting at
different (sites) levels of HIV life Cycle
 Treatment (Therapy)- history
 Mono-therapy - 1986
 Dual-therapy
 Triple-therapy - 1996
 Since 1997 HAART ≥3ARVDs
 Highly Active Anti Retroviral Therapy
 Prevention (prophylaxis)
 PMTCT
 PEP

85.  There are five different classes of ARVDs
 Reverse transcriptase inhibitors
 Nucleotide ~ (NRTIs)
 Non-nucleotide~ (NNRTIs)
 Protease inhibitors
 Entry Inhibitor
 Fusion Inhibitor
 Chemokine Receptor Antagonist
 Attachment Inhibitor
 Integrase Inhibitor

86. Reverse Transcriptase Inhibitors (RTI)
 Nucleoside Reverse Transcriptase Inhibitors
 NRTIs block the RT enzyme (RNA dependent DNA
polymerase) by mimicking the bases that make up DNA
 Non-Nucleoside Reverse Transcriptase Inhibitors
 They stop HIV replication by binding directly onto reverse
transcriptase
 Bind at a different location (allogenic site) than the active site

87. Protease Inhibitors (PIs)
Block the function of the protease enzyme
 Prevent proper cleavage of viral proteins
 Prevent maturation of newly produced virus

88. 88
HIV Receptors
Copyright © 1996 Massachusetts Medical Society. All rights reserved.

89. HIV Life Cycle and Sites
for Therapeutic Drugs
Coreceptor
Blockers
Fusion
Inhibitors
Reverse
Transcriptas
e Inhibitors
Integrase
Inhibitors
Protease
Inhibitors

90. Principles
 Treat/stabilize OIs prior to ART
 Always combination therapy(>/=3ARVS)
 2NRTI+1NNRTI
 2NRTI+ PI
 2NRTI (TDF+FTC) + Raltegravir