Acquired Immunodeficiency

Syndrome (AIDS)

Pan Xiucheng

Department of Infectious Diseases

The Affiliated Hospital
Xu zhou Medical University

1
n I. Definition

§ a fatal and epidemic retroviral disease,

caused by human immunodeficiency virus
HIV

§ transmitted mainly through sexual contact (heterosexual

or homosexual), transfusion with HIV-contaminated blood,
drug injection and mother-to-child transmission.

§ The clinical consequences of whole body’s immune deficiency

are a variety of unusual opportunistic infections and neoplasia .

2
 History

Ø1981: First reports of “Acquired Immuno-

deficiency Syndrome” in Los Angeles.
Ø1983: Virus first isolated in France ( Pasteur Institute)
Ø1984: Virus isolated in the U.S. (called HTLV-
III and AIDS-Related Virus, ARV).
Ø1985: Development and implementation of
antibody test to screen blood donors.

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History
Ø 1992: AIDS becomes the leading cause of death
among adults ages 25-44 in the U.S.
Ø 1997: Mortality rates of AIDS starts to decline due
to the introduction of new drug cocktails.
Ø 2006: World Health Organization(WHO) predicts
up to 40 million infected individuals. More than 22
million have already died.

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 II. Etiology/pathogen

n HIV, types 1 and 2, a RNA virus . HIV-1, major cause of AIDS

worldwide. HIV-2, spreads epidemically in West Africa
n Retrovirus, lentivirus, around 120 nM in diameter, roughly
spherical

n Virion contain 2 copies of a single-stranded RNA genome, RNA

reverse transcriptase and DNA polymerase, some viral proteins
including products of the viral genes env (glycoprotein [gp] gp120,
gp41), gag (p24, p17, p7, p9) and pol (p32, p66, p51, p11)

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Structure of HIV-1
structure of HIV genome
9.7kb

LTR

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 III. Epidemiology

n HIV infection was originally found in United States 1981, now

spreads throughout the world.

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AIDS by the numbers 2015

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 HIV Infection in China
n In mainland of China, HIV prevalence remains low, but
clusters of high prevalence exist.
n By the end of 2016:
HIV prevalence averages 0.06%
HIV infective cases 850,000
AIDS patients 154,000
Newly infected with HIV 48,000
§ Spreading from high risk groups to the general population,
and there is a potential risk that the epidemic will spread
further.
§ The epidemic may continue to increase rapidly over the
coming years, or it may start stabilizing
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Geographical Distribution of HIV Epidemic
in China as of end 2011 感染者数

1-50
51-100
101-500

501-1000
1001-10000
10001-20000
>20000

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 Epidemiology
A Sources of infection
AIDS patients and HIV carrier HIV mainly exists in blood and seminal
fluid, vaginal secretions and other body secretes such as breast milk.
B Routes of transmission
(1) Sexual behavior:
(2) Contaminated blood or blood products transfusion

(3) Intravenous drug injection

(4) Mother to child transmission

（5）Professional exposure
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B Routes of transmission
(1) Sexual behavior:
Ø Predominant mode of HIV transmission over the world.
Ø Unprotected bisexual or homosexual intercourse ,
Ø Other influential factors:
Multiple sexual partners
Higher viremia or advanced AIDS in partner
Presence of other STDs
Receptive anal intercourse
Sexual behavior during menses

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 Epidemiology
B Routes of transmission
(2) Contaminated blood or blood products transfusion:
Ø Blood donations were not tested for HIV

(3) Intravenous drug injection

Ø Sharing contaminated injection
equipment, including needles.

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 Epidemiology

B Routes of transmission
(4) Mother to child transmission
Ø During pregnancy (in uterus) or intrapartum
Ø Delivery or breast-feeding
Ø Depended on viremia and CD4+ cell level of mother
Ø High rates of mother to child transmission 30-40% in
Africa, 15-20% in North America or Europe

(5) Injection-associated nosocomial infection, or other

occupational exposure
Ø Health care workers may be infected through accidents with needle
sticks while caring for patient with HIV
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 Risk Factors for New HIV Infections in China, in
2011

Ø 81.6% sexual transmission

Ø 18.0% injection drug use
Ø 0.4% mother to child transmission
Ø 28.6% Female, 71.4% Male

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 Epidemiology
C High-risk susceptible population
n People with multiple sexual partners, homosexual men
n Commercial sexual workers: male or female prostitute
n Injection drug users
n Contaminated transfusion receptors
n Children with HIV/AIDS mother

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 Pathogenesis/Pathology
n The major targets of HIV infection:
Ø CD4+T lymphocyte, monocytes/macrophage and others CD4+
cells. (B lymphocyte, dendritic cell, stem cell from bone marrow
and so on).
Ø CD4 molecule in target cell membrane is the major receptor for
HIV entry.
Ø 1996, scientists found there were some chemokine receptors (for
example, CCR5 and CXCR4) supporting HIV fusion and entry to
cell.

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 Pathogenesis/Pathology
Life Cycle of HIV
1.Attachment
2. Fusion
3. Uncoating
4. Reverse Transcription
5. Integration
6. Replication
7. Assembly
8. Release
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 Life Cycle of HIV
1. Attachment: protein on the surface of the Virus (protein gp120 and
gp41) binds specifically to protein served as receptors on the surface of T cells
and macrophages.
ØReceptor CD4
ØCoreceptors: CXCR4 and CCR5
ØCXCR4 and CCR5 mutants are resistant to infection.

2. Penetration/Fusion: Viral envelope fuses with cell membrane,

releasing its contents including nucleocapsid and the genetic core into the
cell’s cytoplasm.
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HIV Life Cycle: Attachment Requires CD4
Receptor plus a Coreceptor
 Life Cycle of HIV
3. Uncoating The nucleocapsid needs to been partically
dissolved so that the virus’s RNA can be converted into DNA.

4. Reverse Transcription Viral RNA is converted into

DNA by unique enzyme reverse transcriptase.
Reverse transcriptase
RNA ---------------------> DNA
Reverse transcriptase is the target of several HIV drugs:
AZT, ddI, and ddC.

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HIV Life Cycle: Reverse Transcriptase Converts
RNA into DNA
 Life Cycle of HIV
5. Integration:
Viral DNA is inserted into host cell chromosome by unique
enzyme integrase. Integrated viral DNA may remain latent
for years and is called a provirus.

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HIV Life Cycle: Latent versus Active
Infection
HIV Life Cycle: Latent versus Active
Infection in Macrophages
 HIV Life Cycle

6. Replication: Viral DNA is transcribed and RNA is

translated, making viral proteins.
Viral genome is replicated.
7. Assembly: New viruses are made.
8. Release: New viruses bud through the cell
membrane.

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HIV Life Cycle

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Pathogenesis
attach CD4
HIV CD4+ T cell and CD4+ cells
CCR5 CXCR4

Cellular immune dysfunction

Host immunosuppression

Opportunistic infections,
neoplasmas, and other life-threatening manifestations.

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 Pathogenesis
n Establishment of HIV infection
Ø CD4+T lymphocytes are refractory to HIV replication and
function as latent viral reserviors and then become permissive
for viral replication.
Ø HIV remains latent especially in monocytes/macrophages and
dendritic cells for long periods of time, which resulting in
undiminished viral population.
Ø CCR3 on microglial cells may be important for HIV infection
of the brain.

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 Pathogenesis
Mechanism of HIV-1 persistance
A CD4+T lymphocytes dysfunction
Ø Direct damage
Ø The infected cells become targets of host immune response
Ø The binding of CD4 molecules by the gp120 makes cells lost
their function
Ø the infected CD4 cells fuse with other uninfected cells to form
giant multinucleated cells, leading to dysfunction of the cells
Ø The cross-linking of the CD4 molecules by gp120-anti-gp120
immune complexes may result cell apoptosis or programmed cell
death.
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 Pathogenesis
B Monocyte / macrophage’s and dendritic cell’s
dysfunction and damage

Ø Impaired function of antigen presenting cells(APC)

lead to diminished MHC class1 /antigen presentation
which needed for HIV-specific CTL induction and
decreased recognition of infected cells by HIV-
specific CTL .

Ø Natural killer cell(NK)-mediated killing was inhibited by

infected cells.

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 Pathogenesis
C CD4+B lymphocyte and humoral immune dyfunction
Ø neutralizing antibodies are low and weak
Ø Multi-clone activity
IgG IgA B lymphocyte count

D CD8+ T lymphocyte dyfunction

Ø Early middle later antivral capacity

E Th1 cell response switch to Th-2 cell response

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 Pathogenesis
F Immune escape variant emerge
Ø Selective pressure exerted by HIV-specific CTL

Ø Mutation of viral protein lead to escape from HIV-1

specific CTL

Ø Selective pressure coupled with mutation also will

selcet for variants resistant to neutralizing antibody.

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 Pathogenesis
n Immune escape variant emerge
Ø The inflammatory response that develops following
chronic infection of follicular and interdigitating DCs
result in germinal center destruction and the loss of
antigen-presenting ability within lymph nodes.

Ø Primary HIV-1 infection may induce the production of

low avidity env-specific IgG that has little or no
neutralizing activity.

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 V. Clinical Manifestations
n In clinic, HIV infection can be broken down into
four distinct stages:
(1) Stage 1 Primary HIV infection
(2) Stage 2 Clinical Asymptomatic stage
(3) Stage 3 Symptomatic HIV infection
(4) Stage 4 Progression from HIV to AIDS

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 Clinical Manifestations
n Stage I -- Primary HIV infection

Ø Last for a few weeks

Ø A short flu-like illness
Ø Diagnosis of HIV infection is frequently missed
Ø High levels of HIV RNA,
Ø Anti-HIV maybe negative before seroconversion is
complete window period

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 Clinical Manifestations
n Stage II --Asymptomatic infection
Ø Lasts for an average of ten years
Ø This stage is free from symptoms
Ø There may be swollen glands
Ø The level of HIV in the blood drops to very low levels
Ø HIV is not dormant, but is very active in the lymph nodes.
Ø HIV antibodies or HIV RNA can be detectable in the blood

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 Clinical Manifestations
n Stage III – Symptomatic infection
Ø The immune system deteriorates
Ø The symptoms are initially mild
Ø Emergence of opportunistic infections and cancers
Ø Persistent generalized lymphadenopathy (PGL)
may occur. lymph nodes may be palpable
more than two locations,
Ø last 1-2 years.

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 Clinical Manifestations
n Stage IV --Symptomatic AIDS disease,
ØThe immune system weakens

ØThe illnesses become more

severe leading to an
AIDS diagnosis

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 Opportunistic Infections
associated with AIDS
n Bacterial
n Tuberculosis (TB)
n Strep pneumonia
Kaposi Sarcoma
n Viral
n Kaposi Sarcoma
n Herpes
n Influenza (flu)
Intercostal herpes

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 Opportunistic Infections
associated with AIDS
n Parasite
n Pneumocystis carinii Pneumonia
n Toxoplasma abscess

n Fungal
n Candida Chest X-ray of PCP
n Cryptococcus

Candida cryptococcosis52
 Clinical Manifestations of AIDS

(1) Constitutional disease

(2) Pulmonary manifestation
(3) Skin and mucocutaneous signs
(4) Gastrointestinal manifestations
(5) Neurological and ocular manifestation

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 Clinical Manifestations of AIDS

Constitutional disease:
Fever,
Rash,
Headache,
Loss of weight over 10%
Lymphadenopathy

Emaciated patient in AIDS late stage

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 Clinical Manifestations of AIDS
Pulmonary manifestations:
Ø Lungs are the most frequently affected organs
Ø Lung Disease
caused by virus,bacteria,fungal and nontuberculous mycobacterial infection.
Ø Penumocystis carinii pneumonia (PCP)
Ø Pulmonary Kaposi’s sarcoma (KS)
Ø Lymphoma

Chest X-ray of PCP

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 Clinical Manifestations of AIDS

Pulmonary manifestations:
Ø Clinical characteristics
fever,
non-productive of cough ,
dyspnea, 呼吸困难
tachypnoea 气促
hypoxaemia
respiratory acidosis

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 Clinical Manifestations of AIDS

n Skin and mucocutaneous signs

Ø Mainly result from opportunistic infection
Virus infection : herpesvirus, cytomegalovirus, human papillomavirus,
Epstein- Barr virus(EBV)

Herpes pustulosis

Herpes Zosters Contagious molluscum

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 Clinical Manifestations of AIDS
n Skin and mucocutaneous signs
Ø Fungal infection dermatophytosis 脚癣, candidiasis,
scabies 疥疮, histoplasmosis, cryptococcosis….

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Clinical Manifestations of AIDS
Skin and mucocutaneous signs
Ø Kaposi’s sarcoma

Multiple-Kaposis sarcoma 59
 Clinical Manifestations of AIDS
Gastrointestinal manifestations:

Ø Diarrhea and /or abdominal pain the most frequent symptoms

Ø Pathogens include: cryptosporidia 隐孢子虫, microsporidia,

cytomegalovirus (CMV), mycobacterium avium 鸟分枝杆菌

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 Clinical Manifestations of AIDS
Neurological manifestations:
Ø Infection of virus, bacteria , TB, fungal, cryptococcus and
toxoplasma and lymphoma in CNS
Ø (Meningo) encephalitis （脑膜）脑炎

photophobia 畏光
neck stiffness
headache typically retro-orbital and exacerbated by eye movements
disordered consciousness
depression and changes in mood reflect underlying encephalitis
chorioretinitis and CMV retinitis due to CMV infection in CNS
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 Laboratories’ examination

n Serological tests
Ø HIV antibody ELISA screening of blood sample
possibly false positive or false negative reaction

Ø HIV antigen Western blots the gold standard

Other tests immunofluorescence
RIPA bioassays
P24 antigen screen the blood supply
test for HIV in individuals
diagnose HIV early in the course of infection

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 HIV Infection and Antibody
Response
---Initial Stage---- ---------------Intermediate or Latent Stage-------------- ---Illness Stage---

Flu-like Symptoms
Or Symptom-free AIDS Symptoms
No Symptoms

----

Infection Virus
Occurs
Antibody

----

< 6 month ~ Years ~ Years ~ Years ~ Years

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 Laboratories’ examination
n Plasma HIV viral load
Ø HIV RNA quautification
RT-PCR most representative and sensitive test for
monitoring progression of HIV infection and response to
antiretroviral therapy.
§ Immunologic laboratory tests
Ø CD4 count
<100/mm3 and CD4/CD8 ratio <0.2 prediction for death from AIDS-
related complications

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 Laboratories’ examination

Other examination:
• Chest X-ray for T.B infection , PCP, fungal pneumonia
• Sputum or smear culture , bronchoscopy
• Blood culture and bone marrow culture
• CSF（cerebrospinal fluid） smear and routine for neurological infection
• Lymphatic node biopsy or tissue biopsy for KS and neoplasma
• Endoscopy
• MRI, CT scanning and Ultrasonic scanning
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 Diagnosis
A. Epidemiologic history:
B. Clinical manifestation

C. Evidences in laboratory show as above

WBC T lymphocyte CD4+/CD8+

P24 antigen(+) Gp120 antibody(+) or HIV RNA(+), et al.

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 Diagnosis of clinical AIDS in an adult

Two criteria:
A. Positive test for detection of two different HIV antigen
B. Any one of the following criteria
n Bodyweight loss > 10% or cachexia恶病质
n chronic diarrhea for one month intermittent or constant
n Tuberculosis (disseminated, miliary粟粒状 or extrapulmonary)
n Oesophagus 食道or oral candidiasis
n Neurological impairment restricting daily activities
n Kaposis sarcoma

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Treatments
Principle of treatment
A. General treatment
• Isolation of the patient with symptoms
• supporting treatments and nutrition, medical care , vitamine
supplement and blood transfusion
B. Antiretroviral therapy
C. Immune therapy and gene therapy
D. Treatment of complications

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 Treatments
n Treatment goals:
(1) Reduce HIV-related morbidity and mortality
(2) Improve quality of life
(3) Restore and preserve immunologic function
(4) Maximally and durably suppress viral load
n Predictor of long-term virologic success
(1) potentcy of antiretroviral regimen
(2) adherence to treatment regimen
(3) low baseline viremia, higher baseline CD4+T cell count
(4) rapid reduction of viremia in response to treatment.

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n When to treat
Indications for initiating antiretroviral therapy for the
patient with chronic HIV infection

Clinical category CD4+ cell count Plasma HIV RNA Recommendation

AIDS-defining illness Any value Any value Treat
or severe symptoms
Asymptomatic <200/mm3 Any Value Treat
Asymptomatic >200/mm3 but <350/mm3 Any Value Balance the prons and cons
Asymptomatic >350/mm3 >100,000/ml Most clinicians recommend
deferring therapy, but some
clinicians will treat
Asymptomatic >350/mm3 <100,000/ml Defer therapy

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 Initiate antiretroviral therapy to patients
with acute HIV infection?
Benefits of treatment:
(1) Benificial effect on laboratory marker of disease progression.
(2) Decrease the severity of acute disease and delay progression to AIDS
(3) Decrease bodies’ viral burden(Viremia)
(4) Reduce the rate of viral mutation
(5) Preserve immune function
(6) Reduce the risk for viral transmission
Potential risks:
(1) Drug resistance develop early and future drug’s options limitation
(2) The quality of life reduction and other long-term toxicity
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 Five categories of anti-HIV drugs
n Nucleoside reverse transcriptase inhibitors (NRTI)
To inhibit HIV RT and viral replication
To delay AIDS progression
n Nonnucleoside reverse transcriptase inhibitors (NNRTI)
To inhibit HIV RT by a different way than NRTI,
but easily produce drug resistance
n Protease inhibitors (PI)
To inhibit HIV protease and interfere with viral maturation and assembly
n Integrase inhibitors inhibit the viral enzyme integrase
n Entry inhibitors interfere with binging, fusion and entry of HIV to the host cell
by blocking one of several targets.
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 NRTI
Drug Dose Side effects
Zidovudine 300mg, Bid Nausea, headache, fatigue;
(AZT,ZDV) Anemia, neuropathy,myopathy
Lamivudine 150mg,Bid General
tolerated
( 3TC )
Didanosine 200mg,Bid Peripheral neuropathy,pancreatitis
( ddI )
Zalcitabine 0.75mg/kg,Tid Peripheral neuropathy
( ddC )
Stavudine (d4T) 40mg, Bid
Tenofovirdisoproxil 300mg, qd
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 NNRTI
Drug Dose Side effects

Delavirdine 400mg, Tid Transient rash

Efavirenz 600mg, QN Transient rash, initial dizziness

Nevirapine 200mg, QDx14 Transient rash, hepatitis

200mg, Bid

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 PI
Drug Dose Side effect

Amprenavir 1.2g, Bid Rash, diarrhea, nausea

Indinavir 0.8g, Q8h Kidney stone, nausea
Lopinavir 1.25g, Bid Diarrhea, nausea
Ritonavir 0.6g, Bid Nausea, diarrhea, hepatitis
Saquinavir SGC 1.6g, Bid or
1.2g, Tid

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Integrase inhibitors clinical approved

Raltegravir
Elvitegravir
Dolutegravir

Entry inhibitors clinical approved

Maraviroc
Enfuvirtide

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Combination Therapy
v Goals:
n To enhance inhibition of viral replication
n To reduce or delay HIV mutation and drug resistance
n To reduce drug toxicities and side-effect.
v Highly active antiretroviral therapy, HAART
n Available for adults, children, pregnant women
HIV/AIDS persons.
n Recommended combination is two NRTI-one PI, or two
NRTI-one NNRTI, or three NRTI NNRTI based regimens
are commonly prescribed as initial therapy for treatment naive patients.

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D. Treatment of complications
§ Pneumocystis carinii pneumonia (PCP)
Ø Trimethoprim-sulfamethoxazole (TMP/SMZ) first choice
Ø TMP/SMZ+ corticosteroids
use corticosteroids as early as possible to patient with moderate –to-
severe disease after treatment of PCP with TMP/SMZ
§ Toxoplasma gondii encephalitis(TE)
Ø Pyrimethamine 乙胺嘧啶 +sulfadiazine磺胺嘧啶+leucovorin 叶酸

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D. Treatment of complications
§ Cryptosporidiosis 隐孢子虫病
Ø No specific drug for treatment of cryptosporidiosis
Ø Effective ART treatment
Ø Symptomatic treatment diarrhea, rehydration and repletion of
electrolyte losses
§ Mycobacterium tuberculosis disease
Ø Follow the general principles developed for TB treatment among non-HIV-
infected persons
Ø Early diagnosis and treatment are critical.
Ø Directly Observed therapy(DOT) is strongly recommended for pts with HIV-1-
related TB

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D. Treatment of complications
n Bartonellosis 巴尔通体病

Ø Erythromycin 红霉素, doxycycline 强力霉素 first-line treatment

Ø Doxycyline used to patient with central nervous system bartonellosis
Ø Clarithromycin 克拉霉素 azithromycin 阿奇霉素 second line alternatives
§ Mucocutaneous candidiasis
Ø Fluconazole 氟康唑, itraconazole 伊曲康唑
Ø At least 14-21 day course of treatment

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D. Treatment of complications
§ Cryptococcosis
Ø Amphotericin B or Liposomal of Amphotericin
Ø Amphotericin B plus flucytosine 氟胞嘧啶
2 week duration followed by flucytosine alone for additional 8 weeks
§ Histoplasmosis
Ø Amphotericin B, either the deoxycholate formulation or liposomal
Amphotericin B
Ø Itraconazole used for pts who cannot tolerate Amphotericin B

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D. Treatment of complications
§ Cytomegalovirus (CMV) disease
Ø Oral valganciclovir 缬更昔洛韦
Ø Intravenous ganciclovir
Ø Intravenous ganciclovir followed by Oral valganciclovir
Ø Intravenous foscarnet 膦甲酸钠
Ø Intravenous cidofovir 西多福韦

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D. Treatment of complications
§ Kaposi’s sarcoma (KS)
Ø Cryosurgery
Ø Vinca alkaloids 长春新碱
Ø Intralesional bleomycin 博来霉素
Ø Intralesional interferons
Ø Soft x-ray radiation
Ø Electron beam therapy
Ø Cobalt radiation
Ø Retinoid 维甲酸

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 Prognosis
l Without treatment
ü Survival time(net median) after HIV infection 9-11 years
ü Survival time (median) after diagnosis of AIDS within 1 year

l Effective therapy (HAART)

ü Reduced the death rate 80%
ü Raised the life expectancy 20-50years

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Prophylaxis
A. Control sources infection
n Isolation of HIV/AIDS person and antiretrovirao
treatment
n Blood donor screening
n Powerful sterilization of HIV contaminated blood and
excrement
n Border quarantine
B. Protect susceptible population
n Avoid HIV women’s pregnancy
n Satisfactory vaccine is not available
n Education programs for high risk population 85
C. Block routes of transmission
n Promote safe sexual practices
Consistent condom use
Reduction of the number of partners
Treatment of other STDs
n Reduce transmission by injection
Methadone 美沙酮 maintenance program
Using sterile equipment or disposable syringe
Needle/syringe exchange program
Eliminating needle sharing 86
n Block mother-to-child transmission
Ø Antiviral treatment for HIV-infected pregnant women
AZT +3TC or NVP
Ø Heating milk feeding or artificial feeding
Ø Caesarean operation
n Prevent occupational exposures
Ø Dispose needle/syringe
Ø Strict sterilization for diagnostic and treating equipments
Ø Sterilization for HIV contaminated blood and body fluids
Ø Post exposure prophylaxis with antiviral medications as soon as
possible after exposure to HIV but certainly within 72 hours. Treatment with 2 or 3
ARTs should continue for 4 weeks.
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Thorax rash
Neck lymphadenopathy
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Ulceration of lymph nodes and multi-furunculosis
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Man’s genitals ulcerations
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Woman’s genitals ulcerations
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Thrush (oral candidiasis)
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 Crural
Kaposis sarcoma

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Crural Kaposis sarcoma
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Hepatomegaly

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Chest X-ray
Examination
( pneumocystis
carinii
pneumonia,
PCP)

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Progressive multifocal leukoencephalopathy
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