Distribution of HIV-1 subtypes

HIV-1 subtypes Distribution

Important adaptations have been necessary for the virus to acquire the ability to be efficiently transmitted. Since its emergence, HIV-1 group M has diverged into numerous clades or subtypes (A to K) as well as circulating recombinant forms (CRFs). CRFs have segments of the genome derived from more than one subtype. The highest diversity of HIV remains in west-central Africa, the region where HIV originated. Despite the potential for divergent viruses to spread, only a few viruses have successfully expanded with 90% of the epidemic comprising of just four subtypes (A, B, C and D) and two CRFs (CRF01_AE and CRF02_AG). Currently, subtype C, subtype A, and CRF02_AG together account for majority of thousands of new infections that occur daily worldwide. Historically, many more viruses should have been emerged from Africa but failed establish themselves within transmission networks, or were of lower fitness which limited their dispersal.

The amino acid distances among different subtypes of HIV-1 group M reach approximately 25–30% in the Env gene sequence and 15% in the Gag gene sequence. The subtypes B and D are better considered as subsubtypes within a single subtype, however they have been designated as subtypes for historical reasons. To define a new subtype, subsubtype or CRF, the representative strains must be identified in at least three epidemiologically unlinked individuals. Three near full length genomic sequences are preferred, but two complete genomes with partial sequences of a third strain are sufficient to designate a new subtype, subsubtype or CRF.

Regarding HIV in the Americas, subtype B was the first to appear in the United States and the Caribbean and still remains the most prevalent (98.0%) throughout the region. One study demonstrated that the epidemic originated in Haiti around 1966 and within 5 years a single transmission event occurred that culminated in the subtype B epidemic in the US. The spread of AIDS from Kinshasa and Congo to Haiti can be explained by hundreds of educational technicians working there for UNESCO between 1960 and 1975. All were single and returned regularly on holiday to Haiti.

Distribution of HIV-1 subtypes

Group	Subtype	Distribution
Group	Subtype	Distribution
M	A	East and Central Africa
	B	North and South Africa, Europe, Asia, Oceania
	C	South and East Africa, India, Brazil
	D	Central Africa
	F	Central Africa, Romania, Latin America
	G	Central Africa, Taiwan, Russia
	H	Central Africa, Belgium
	J	Congo, Gambia, Sweden
	K	Cameroon
O		Cameroon, Gabon, France
N		Cameroon

The most prevalent HIV-1 genotypes are subtypes C (47%), A (27.2%), B (12.3%), D (5.3%) and CRF01_AE (3.2%).

 During the AIDS pandemic, it has become clear that host genetic differences between infected individuals as well as between viral species affect the susceptibility or resistance to the disease, revealing a clinical spectrum of rapid, intermediate, or slow progression or, more rarely, nonprogression to AIDS within infected populations.

Human Immunodeficiency Virus 1 (HIV-1)

Origin

The analysis of two archival HIV-positive samples collected in 1959 and 1960 on territory of the Democratic Republic of the Congo (previously Zaire) showed that at that time the group M viruses had already diversified significantly suggesting that they had been evolving in humans since 1902–1921.

In Africa, many species of indigenous nonhuman primates are naturally infected with related lentiviruses. Primates and the viruses co-evolved for very long time and as a result of mutual adaptations infections do not usually lead to AIDS-lile conditions despite of high plasma viral loads and sustained viral evolution.
Molecular phylogeny studies reveal that HIV-1 evolved from a strain of simian immunodeficiency virus, SIVcpz, within a particular subspecies of the chimpanzee (Pan troglodytes troglodytes). HIV-2 originated from SIVsm of sooty mangabeys (Cercocebus atys). Because SIV is a bloodborne pathogen and is also present in cells of mucous epithelium, humans could have been exposed to SIV on many occasions through bites, scratches, and wounds during hunting or other activities that involve monkeys and apes. The virus might have crossed primate-human barrier multiple times and at least on three separate occasions it was able to establish itself in the human organism at levels sufficient to become transmissible within the local human population resulting in three distinct phylogenetic lineages: M (Major, Main), N (New, Non-M, Non-O), and O (Outlier). O and N viruses are not pandemic. Thus, among the three SIVcpz ancestors of HIV-1 that have successfully crossed to humans, only one has given rise to the global AIDS pandemic: HIV-1 group M with subtypes A to K. Elegant field and phylogenetic studies determined that HIV-1 groups M and N (New) arose from geographically distinct chimpanzee populations in Cameroon however epicenter of human infections occured probably in Congo-Kinshasa (Zaire), Rwanda and Burundi. The origin of group O remains to be identified, but given the location of human cases, cross-species transmission may have occurred in neighboring Gabon. Group O viruses are most closely related to viruses infecting gorillas, and studies suggest that the gorillas acquired viruses from chimpanzees. are also the origin of infection of these gorillas. Similar to HIV-2, HIV-1 group O viruses are known to be naturally resistant to non-nucleoside RT (reverse transcriptase) inhibitors (NNRTs). Only a few cases of group N infections have been identified, and these were in patients from Cameroon.

Three hypotheses of global pandemic exist:

1. The virus was transmitted to humans in the 1800s or early 1900s. It then would have remained isolated in a small, local human population until about 1930s, when it began spreading to other human populations and to diversify (Transmission Early Hypothesis).
2. The virus was transmitted from chimpanzees to humans around 1930, and immediately began to spread and diversify in human populations (Transmission Causes Epidemic Hypothesis).
3. Multiple strains of SIV were transmitted from chimpanzees to humans in the 1940s or 1950s (Parallel Late Transmisson Hypothesis). 

It has been suggested that parallel transmission could have occured through oral poliovirus vaccinations adminestered in Central Africa between 1957 and 1960. Poliovirus was cultured in chimpanzee kidney cells that could have been contaminated with multiple SIVs. This hypothesis, however, does not withstand close scrutiny.

CDC Classification System

Examples include, but are not limited to, the following:

• Bacillary angiomatosis
• Oropharyngeal candidiasis (thrush)
• Vulvovaginal candidiasis, persistent or resistant
• Pelvic inflammatory disease (PID)
• Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
• Hairy leukoplakia, oral
• Idiopathic thrombocytopenic purpura
• Constitutional symptoms, such as fever (>38.5°C) or diarrhea lasting >1 month
• Peripheral neuropathy
• Herpes zoster (shingles), involving ≥2 episodes or ≥1 dermatome

CDC Classification System: Category C AIDS-Indicator Conditions

• Bacterial pneumonia, recurrent (≥2 episodes in 12 months)
• Candidiasis of the bronchi, trachea, or lungs
• Candidiasis, esophageal
• Cervical carcinoma, invasive, confirmed by biopsy
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary
• Cryptosporidiosis, chronic intestinal (>1-month duration)
• Cytomegalovirus disease (other than liver, spleen, or nodes)
• Encephalopathy, HIV-related
• Herpes simplex: chronic ulcers (>1-month duration), or bronchitis, pneumonitis, or esophagitis
• Histoplasmosis, disseminated or extrapulmonary
• Isosporiasis, chronic intestinal (>1-month duration)
• Kaposi sarcoma
• Lymphoma, Burkitt, immunoblastic, or primary central nervous system
• Mycobacterium avium complex (MAC) or M kansasii , disseminated or extrapulmonary
• Mycobacterium tuberculosis , pulmonary or extrapulmonary
• Mycobacterium , other species or unidentified species, disseminated or extrapulmonary
• Pneumocystis jiroveci (formerly carinii ) pneumonia (PCP)
• Progressive multifocal leukoencephalopathy (PML)
• Salmonella septicemia, recurrent (nontyphoid)
• Toxoplasmosis of brain
• Wasting syndrome due to HIV (involuntary weight loss >10% of baseline body weight) associated with either chronic diarrhea (≥2 loose stools per day ≥1 month) or chronic weakness and documented fever ≥1 month

WHO Clinical Staging of HIV/AIDS and Case Definition

The clinical staging and case definition of HIV for resource-constrained settings were developed by the WHO in 1990 and revised in 2007. Staging is based on clinical findings that guide the diagnosis, evaluation, and management of HIV/AIDS, and does not require a CD4 cell count. This staging system is used in many countries to determine eligibility for antiretroviral therapy, particularly in settings in which CD4 testing is not available. Clinical stages are categorized as 1 through 4, progressing from primary HIV infection to advanced HIV/AIDS (Table 4). These stages are defined by specific clinical conditions or symptoms. For the purpose of the WHO staging system, adolescents and adults are defined as individuals aged ≥15 years.

WHO Clinical Staging of HIV/AIDS for Adults and Adolescents

Primary HIV Infection

• Asymptomatic
• Acute retroviral syndrome

Clinical Stage 1

• Asymptomatic
• Persistent generalized lymphadenopathy

Clinical Stage 2

• Moderate unexplained weight loss (<10% of presumed or measured body weight)
• Recurrent respiratory infections (sinusitis, tonsillitis, otitis media, and pharyngitis)
• Herpes zoster
• Angular cheilitis
• Recurrent oral ulceration
• Papular pruritic eruptions
• Seborrheic dermatitis
• Fungal nail infections

Clinical Stage 3

• Unexplained severe weight loss (>10% of presumed or measured body weight)
• Unexplained chronic diarrhea for >1 month
• Unexplained persistent fever for >1 month (>37.6°C, intermittent or constant)
• Persistent oral candidiasis (thrush)
• Oral hairy leukoplakia
• Pulmonary tuberculosis (current)
• Severe presumed bacterial infections (eg, pneumonia, empyema, pyomyositis, bone or joint infection, meningitis, bacteremia)
• Acute necrotizing ulcerative stomatitis, gingivitis, or periodontitis
• Unexplained anemia (hemoglobin <8 g/dL)
• Neutropenia (neutrophils <500 cells/µL)
• Chronic thrombocytopenia (platelets <50,000 cells/µL)

Clinical Stage 4

• HIV wasting syndrome, as defined by the CDC (see Table 3, above)
• Pneumocystis pneumonia
• Recurrent severe bacterial pneumonia
• Chronic herpes simplex infection (orolabial, genital, or anorectal site for >1 month or visceral herpes at any site)
• Esophageal candidiasis (or candidiasis of trachea, bronchi, or lungs)
• Extrapulmonary tuberculosis
• Kaposi sarcoma
• Cytomegalovirus infection (retinitis or infection of other organs)
• Central nervous system toxoplasmosis
• HIV encephalopathy
• Cryptococcosis, extrapulmonary (including meningitis)
• Disseminated nontuberculosis Mycobacteria infection
• Progressive multifocal leukoencephalopathy
• Candida of the trachea, bronchi, or lungs
• Chronic cryptosporidiosis (with diarrhea)
• Chronic isosporiasis
• Disseminated mycosis (eg, histoplasmosis, coccidioidomycosis, penicilliosis)
• Recurrent nontyphoidal Salmonella bacteremia
• Lymphoma (cerebral or B-cell non-Hodgkin)
• Invasive cervical carcinoma
• Atypical disseminated leishmaniasis
• Symptomatic HIV-associated nephropathy
• Symptomatic HIV-associated cardiomyopathy
• Reactivation of American trypanosomiasis (meningoencephalitis or myocarditis)

HIV Classification

HIV Classification: CDC and WHO Staging Systems

CDC Classification System for HIV Infection

WHO Clinical Staging of HIV/AIDS and Case Definition

CDC Classification System for HIV-Infected Adults and Adolescents

CDC Classification System: Category B Symptomatic Conditions

CDC Classification System: Category C AIDS-Indicator Conditions

WHO Clinical Staging of HIV/AIDS for Adults and Adolescents

Background

HIV disease staging and classification systems are critical tools for tracking and monitoring the HIV epidemic and for providing clinicians and patients with important information about HIV disease stage and clinical management. Two major classification systems currently are in use: the U.S. Centers for Disease Control and Prevention (CDC) classification system and the World Health Organization (WHO) Clinical Staging and Disease Classification System..

The CDC disease staging system (last revised in 1993) assesses the severity of HIV disease by CD4 cell counts and by the presence of specific HIV-related conditions. The definition of AIDS includes all HIV-infected individuals with CD4 counts of <200 cells/µL (or CD4 percentage <14%) as well as those with certain HIV-related conditions and symptoms. Although the fine points of the classification system rarely are used in the routine clinical management of HIV-infected patients, a working knowledge of the staging criteria (in particular the definition of AIDS) is useful in patient care. In addition, the CDC system is used in clinical and epidemiologic research. 

In contrast to the CDC system, the WHO Clinical Staging and Disease Classification System (revised in 2005) can be used readily in resource-constrained settings without access to CD4 cell count measurements or other diagnostic and laboratory testing methods. The WHO system classifies HIV disease on the basis of clinical manifestations that can be recognized and treated by clinicians in diverse settings, including resource-constrained settings, and by clinicians with varying levels of HIV expertise and training. 

S:

When a patient presents with a diagnosis of HIV infection, review the patient's history to elicit and document any HIV-related illnesses or symptoms.

O:

Perform a complete physical examination and appropriate laboratory studies (see chapters Initial Physical Examination and Initial and Interim Laboratory and Other Tests).

A:

Confirm HIV infection and perform staging.

P:

Evaluate symptoms, history, physical examination results, and laboratory results, and make a staging classification according to the CDC or WHO criteria (see below).

CDC Classification System for HIV Infection

The CDC categorization of HIV/AIDS is based on the lowest documented CD4 cell count (Table 1) and on previously diagnosed HIV-related conditions (Tables 2 and 3). For example, if a patient had a condition that once met the criteria for Category B but now is asymptomatic, the patient would remain in Category B. Additionally, categorization is based on specific conditions, as indicated below. Patients in categories A3, B3, and C1-C3 are considered to have AIDS.

CDC Classification System for HIV-Infected Adults and Adolescents

Key to abbreviations: CDC = U.S. Centers for Disease Control and Prevention; PGL = persistent generalized lymphadenopathy. # For symptomatic conditions. * For AIDS-indicator conditions.
CD4 Cell Categories	Clinical Categories
	A Asymptomatic, Acute HIV, or PGL	B Symptomatic Conditions,#* not A or C	C AIDS-Indicator Conditions*
(1) ≥500 cells/µL	A1	B1	C1
(2) 200-499 cells/µL	A2	B2	C2
(3) <200 cells/µL	A3	B3	C3

CDC Classification System: Category B Symptomatic Conditions

Category B symptomatic conditions are defined as symptomatic conditions occurring in an HIV-infected adolescent or adult that meet at least 1 of the following criteria:

a)   They are attributed to HIV infection or indicate a defect in cell-mediated immunity.

b)   They are considered to have a clinical course or management that is complicated by HIV infection.